Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant agent

ABSTRACT

Disclosed in certain embodiments is an oral dosage form comprising:
     a therapeutically effective amount of an opioid analgesic; an opioid antagonist; and   an irritant in an effective amount to impart an irritating sensation to an abuser upon administration of the dosage form after tampering.

This application claims the benefit of U.S. Provisional Ser. No.60/310,515, filed Aug. 6, 2001, hereby incorporated by reference in itsentirety.

BACKGROUND OF THE INVENTION

Opioid analgesics are sometimes the subject of abuse. Typically, aparticular dose of an opioid analgesic is more potent when administeredparenterally as compared to the same dose administered orally.Therefore, one popular mode of abuse of oral opioid formulationsinvolves the extraction of the opioid from the dosage form, and thesubsequent injection of the opioid (using any “suitable” vehicle forinjection) in order to achieve a “high.”

In the prior art, there have previously been attempts to control theabuse potential associated with opioid analgesics. For example, thecombination of immediate release pentazocine and naloxone has beenutilized in tablets available in the United States, commerciallyavailable as Talwin®Nx from Sanofi-Winthrop. Talwin®Nx is indicated forthe relief of moderate to severe pain. Talwin®Nx contains immediaterelease pentazocine hydrochloride equivalent to 50 mg base and naloxonehydrochloride equivalent to 0.5 mg base. The amount of naloxone presentin this combination has low activity when taken orally, and minimallyinterferes with the pharmacologic action of pentazocine. However, thisamount of naloxone given parenterally has profound antagonistic actionto narcotic analgesics. Thus, the inclusion of naloxone is intended tocurb a form of misuse of oral pentazocine which occurs when the dosageform is solubilized and injected. Therefore, this dosage has lowerpotential for parenteral misuse than previous oral pentazocineformulations.

A fixed combination therapy comprising tilidine (50 mg) and naloxone (4mg) has been available in Germany for the management of severe painsince 1978 (Valoron®N, Goedecke). The rationale for the combination ofthese drugs is effective pain relief and the prevention of tilidineaddiction through naloxone-induced antagonisms at the morphine receptor.A fixed combination of buprenorphine and naloxone was introduced in 1991in New Zealand (Temgesic®Nx, Reckitt & Colman) for the treatment ofpain.

Purdue Pharma L.P currently markets sustained-release oxycodone indosage forms containing 10, 20, 40, and 80 mg oxycodone hydrochlorideunder the tradename OxyContin.

U.S. Pat. Nos. 5,266,331; 5,508,042; 5,549,912 and 5,656,295 disclosesustained release oxycodone formulations.

U.S. Pat. Nos. 4,769,372 and 4,785,000 to Kreek describe methods oftreating patients suffering from chronic pain or chronic cough withoutprovoking intestinal dysmotility by administering 1 to 2 dosage unitscomprising from about 1.5 to about 100 mg of opioid analgesic orantitussive and from about 1 to about 18 mg of an opioid antagonisthaving little to no systemic antagonist activity when administeredorally, from 1 to 5 times daily.

U.S. Pat. No. 6,228,863 to Palermo et al. describes compositions andmethods of preventing abuse of opioid dosage forms.

WO 99/32119 to Kaiko et al. describes compositions and methods ofpreventing abuse of opioid dosage forms.

U.S. Pat. No. 5,472,943 to Crain et al. describes methods of enhancingthe analgesic potency of bimodally acting opioid agonists byadministering the agonist with an opioid antagonist.

Additionally, Shaw et al., U.S. Pat. No. 3,980,766, relates to drugswhich are suitable for therapy in the treatment of narcotic drugaddiction by oral use, e.g., methadone, formulated to prevent injectionabuse through concentration of the active component in aqueous solutionby incorporating in a solid dosage or tablet form of such drug aningestible solid having thickening properties which cause rapid increasein viscosity upon concentration of an aqueous solution thereof.

However, there still exists a need for a safe and effective treatment ofpain with opioid analgesic dosage forms which are less subject to abusethan current therapies.

All documents cited herein, including the foregoing, are incorporated byreference in their entireties for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of certain embodiments of the invention to provide oraldosage form of an opioid analgesic which is subject to less parenteralabuse than other dosage forms.

It is an object of certain embodiments of the invention to provide anoral dosage form of an opioid analgesic which is subject to lessintranasal abuse than other dosage forms.

It is an object of certain embodiments of the invention to provide anoral dosage form of an opioid analgesic which is subject to less oralabuse than other dosage forms.

It is a further object of certain embodiments of the invention toprovide an oral dosage form of an opioid analgesic which is subject toless diversion than other dosage forms.

It is a further object of certain embodiments of the invention toprovide a method of treating pain in human patients with an oral dosageform of an opioid analgesic while reducing the abuse potential of thedosage form.

It is a further object of certain embodiments of the invention toprovide a method of manufacturing an oral dosage form of an opioidanalgesic such that it has less abuse potential.

These objects and others are achieved by the present invention, which isdirected in part to an oral dosage form comprising an opioid analgesic;an opioid antagonist; and at least one aversive agent for reducing theabuse of the opioid analgesic.

In certain embodiments of the present invention, the oral dosage formsof the present invention comprising an opioid analgesic; an opioidantagonist; and an aversive agent or agents as a component(s) of thedosage form helps to prevent injection abuse by decreasing the“attractiveness” of the dosage form to a potential abuser.

In certain embodiments of the present invention, the dosage formcomprises an aversive agent such as a bittering agent to discourage anabuser from tampering with the dosage form and thereafter inhaling orswallowing the tampered dosage form. Preferably, the bittering agent isreleased when the dosage form is tampered with and provides anunpleasant taste to the abuser upon inhalation and/or swallowing of thetampered dosage form.

In certain embodiments of the present invention, the dosage formcomprises an aversive agent such as an irritant to discourage an abuserfrom tampering with the dosage form and thereafter inhaling, injecting,or swallowing the tampered dosage form. Preferably, the irritant isrelease when the dosage form is tampered with and provides a burning orirritating effect to the abuser upon inhalation, injection, and/orswallowing the tampered dosage form.

In certain embodiments of the present invention, the dosage formcomprises an aversive agent such as a gelling agent to discourage anabuser from tampering with the dosage form and thereafter inhaling,injecting, or swallowing the tampered dosage form. Preferably, thegelling agent is released when the dosage form is tampering with andprovides a gel-like quality to the tampered dosage form which slows theabsorption of the opioid analgesic such that an abuser is less likely toobtain a rapid “high”. In certain preferred embodiments, when the dosageform is tampered with and exposed to a small amount (e.g., less thanabout 10 ml) of an aqueous liquid (e.g., water), the dosage form will beunsuitable for injection and/or inhalation. Upon the addition of theaqueous liquid, the tampered dosage form preferably becomes thick andviscous, rendering it unsuitable for injection. The term “unsuitable forinjection” is defined for purposes of the present invention to mean thatone would have substantial difficulty injecting the dosage form (e.g.,due to pain upon administration or difficulty pushing the dosage formthrough a syringe) due to the viscosity imparted on the dosage form,thereby reducing the potential for abuse of the opioid analgesic in thedosage form. In certain embodiments, the gelling agent is present insuch an amount in the dosage form that attempts at evaporation (by theapplication of heat) to an aqueous mixture of the dosage form in aneffort to produce a higher concentration of the therapeutic agent,produces a highly viscous substance unsuitable for injection.

When nasally inhaling the tampered dosage form, the gelling agent canbecome gel like upon administration to the nasal passages due to themoisture of the mucous membranes. This also makes such formulationsaversive to nasal administration, as the gel will stick to the nasalpassage and minimize absorption of the abusable substance.

In certain embodiments of the present invention, the dosage formcomprises a combination of any or all of the aforementioned aversiveagents (e.g., a bittering agent, an irritant, and/or a gelling agent) todiscourage an abuser from tampering with the dosage form and thereafterinhaling, injecting, and/or swallowing the tampered dosage form.

Embodiments specifically contemplated include bittering agent; gellingagent; irritant; bittering agent and gelling agent; bittering agent andirritant; gelling agent and irritant; bittering agent and gelling agent;bittering agent and irritant; gelling agent and irritant; and bitteringagent and gelling agent and irritant.

In certain preferred embodiments, the dosage forms are controlledrelease oral dosage forms comprising a therapeutically effective amountof an opioid analgesic and an opioid antagonist together with one ormore of the aversive agents described above such that the dosage formprovides effective pain relief for at least about 12 hours, or at leastabout 24 hours, when orally administered to a human patient.

In certain embodiments of the present invention the opioid antagonistpresent in the dosage form is present in a substantially non-releasableform (i.e., “sequestered”) when the dosage form is administered intactas directed. Preferably, because the opioid antagonist is present in thedosage form in a substantially non-releasable form, it does notsubstantially block the analgesic effect of the opioid agonist when thedosage form is orally administered intact, and does not pose a risk ofprecipitation of withdrawal in opioid tolerant or dependent patients.

In certain embodiments of the present invention, the aversive agentpresent in the dosage form is present in a substantially non-releasableform (i.e., “sequestered”) instead of, or in addition to, the opioidantagonist being in a substantially non-releasable form.

In other embodiments, the aversive agent may not be “sequestered” asdisclosed above wherein the aversive agent is not released or minimallyreleased from an intact dosage form, but may have a modified orsustained release so as not to dump the aversive agent in a particularsection of the gastrointestinal tract; e.g. the stomach, where it maycause an unwanted effect such as excessive irritation. The aversiveagent can be combined with an enteric carrier to delay its release orcombined with a carrier to provide a sustained release of the aversiveagent. However, it is contemplated in the present invention that theaversive agent will preferably not have any significant side effect(e.g., gastrointestinal side effect) even if all of the aversive agentis immediately released upon oral administration of an intact dosageform as directed. The aversive agent(s) can also be in the dosage formin releasable form and non-releasable form in any combination. Forexample, a dosage form can have a bittering agent, irritant, gel orcombination thereof in releasable form and non-releasable form asdisclosed in U.S. patent application entitled “Compositions And MethodsTo Prevent Abuse Of Opioids” filed Aug. 6, 2002. Likewise, theantagonist of the present invention may be in releasable form,non-releasable form or a combination of releasable form andnon-releasable form as disclosed in U.S. patent application entitled“Pharmaceutical Formulations Containing Opioid Agonist, ReleasableAntagonist, and Sequestered Antagonist” filed Aug. 6, 2002 and herebyincorporated by reference in its entirety, in combination with one ofthe aversive agents disclosed herein.

For example, the antagonist of the present invention can be anantagonist with minimal oral activity such as naloxone in releasable or“non-sequestered” farm. The inclusion of such an antagonist would be adeterrent to parenteral abuse of the dosage form and the aversive agentsof the present invention (i.e., bittering agent, irritant, gellingagent) would be a deterrent to oral and nasal abuse of the dosage form.In addition, the dosage form can contain a “sequestered” antagonist suchas a bioavailable antagonist to further deter the oral and nasal abuseof the dosage form upon administration of a tampered dosage form.

The term “aversive agent” is defined for purposes of the presentinvention to mean a bittering agent, an irritant, or a gelling agent.

The term “tampered dosage form” is defined for purposes of the presentinvention to mean that the dosage form has been manipulated bymechanical, thermal, and/or chemical means which changes the physicalproperties of the dosage form, e.g., to liberate the opioid agonist forimmediate release if it is in sustained release form, or to make theopioid agonist available for inappropriate use such as administration byan alternate route, e.g., parenterally. The tampering can be, e.g., bymeans of crushing, shearing, grinding, chewing, dissolution in asolvent, heating, (e.g., greater than about 45° C.), or any combinationthereof.

The term “substantially non-releasable form” for purposes of the presentinvention refers to an opioid antagonist and/or aversive agent that isnot released or substantially not released at one hour after the intactdosage form containing an opioid agonist, an opioid antagonist and atleast one aversive agent is orally administered (i.e., without havingbeen tampered with). Formulations comprising an opioid antagonist in adosage form in a substantially non-releasable form are described in U.S.application Ser. No. 09/781,081, entitled “Tamper Resistant Oral OpioidAgonist Formulations”, filed Feb. 8, 2001, the disclosure of which ishereby incorporated by reference in its entirety. For purposes of thepresent invention, the amount released after oral administration of theintact dosage form may be measured in-vitro via the dissolution at 1hour of the dosage form in 900 ml of Simulated Gastric Fluid using a USPType II (paddle) apparatus at 75 rpm at 37° C. Such a dosage form isalso referred to as comprising a “sequestered antagonist” and/or a“sequestered aversive agent” depending on the agent or agents which arenot released or substantially not released. In certain preferredembodiments of the invention, the substantially non-releasable form ofthe antagonist and/or the aversive agent is resistant to laxatives(e.g., mineral oil) used to manage delayed colonic transit and resistantto achlorhydric states. Preferably, the aversive agent is not releasedor not substantially released 4, 8, 12 and/or 24 hours after oraladministration.

The phrase “at least partially blocking the opioid effect”, is definedfor purposes of the present invention to mean that the opioid antagonistat least significantly blocks the euphoric effect of the opioidantagonist, thereby reducing the potential for abuse of the opioidagonist in the dosage form.

The phrase “analgesic effectiveness” is defined for purposes of thepresent invention as a satisfactory reduction in or elimination of pain,along with a tolerable level of side effects, as determined by the humanpatient.

The phrase “not substantially blocking the analgesic effect of an opioidagonist” for purposes of the present invention means that the opioidantagonist does not block the effects of the opioid agonist insufficient degree as to render the dosage form therapeutically lesseffective for providing analgesia.

The term “sustained release” is defined for purposes of the presentinvention as the release of the opioid analgesic from the oral dosageform at such a rate that blood (e.g., plasma) concentrations (levels)are maintained within the therapeutic range but below toxic levels overan extended period of time, e.g., from about 12 to about 24 hours ascompared to an immediate release product. Preferably the sustainedrelease is sufficient to provide a twice-a-day or a once-a-dayformulation.

The term “particles” of opioid antagonist, as used herein, refers togranules, spheroids, beads or pellets comprising the opioid antagonist.In certain preferred embodiments, the opioid antagonist particles areabout 0.2 to about 2 mm in diameter, more preferably about 0.5 to about2 mm in diameter.

The term “parenterally” as used herein includes subcutaneous injections,intravenous injections, intramuscular injections, intrasternalinjections, infusion techniques, or other methods of injection known inthe art.

The term “inhaled” as used herein includes trans-mucosal,trans-bronchial, and trans-nasal abuse.

The term “bittering agent” as used herein includes a compound used toimpart a bitter taste, bitter flavor, etc., to an abuser administering atampered dosage form of the present invention.

The term “irritant” as used herein includes a compound used to input anirritating, e.g., burning or uncomfortable, sensation to an abuseradministering a tampered dosage form of the present invention.

The term “gelling agent” as used herein includes a compound orcomposition used to impart gel-like or thickening quality to a tampereddosage form upon the addition of moisture or liquid.

DETAILED DESCRIPTION OF THE INVENTION

The aversive agents of the present invention are preferably for use inconnection with oral dosage forms including opioid analgesics and opioidantagonists, which provide valuable analgesia but which may be abused.This is particularly true for controlled release opioid analgesicproducts which have a large dose of a desirable opioid analgesicintended to be released over a period of time in each dosage unit. Drugabusers typically may take a controlled-release product and crush,shear, grind, chew, dissolve and/or heat, extract or otherwise damagethe product so that the full contents of the dosage form becomeavailable for immediate absorption by injection, inhalation, and/or oralconsumption.

In certain embodiments, the present invention comprises a method forpreventing or deterring of the abuse of opioid analgesics by theinclusion of an opioid antagonist and at least one aversive agent in thedosage form with the opioid analgesic.

In certain embodiments of the present invention wherein the dosage formincludes an aversive agent comprising a bittering agent, variousbittering agents can be employed including, for example and withoutlimitation, natural, artificial and synthetic flavor oils and flavoringaromatics and/or oils, oleoresins and extracts derived from plants,leaves, flowers, fruits, and so forth, and combinations thereof.Nonlimiting representative flavor oils include spearmint oil, peppermintoil, eucalyptus oil, oil of nutmeg, allspice, mace, oil of bitteralmonds, menthol and the like. Also useful bittering agents areartificial, natural and synthetic fruit flavors such as citrus oilsincluding lemon, orange, lime, grapefruit, and fruit essences and soforth. Additional bittering agents include sucrose derivatives (e.g.,sucrose octaacetate), chlorosucrose derivatives, quinine sulphate, andthe like The preferred bittering agent for use in the present inventionis Denatonium Benzoate NF-Anhydrous, sold under the name Bitrex™(Macfarlan Smith Limited, Edinburgh, UK).

With the inclusion of a bittering agent in the formulation, the intakeof the tampered with dosage form produces a bitter taste upon inhalationor oral administration which in certain embodiments spoils or hindersthe pleasure of obtaining a high from the tampered dosage form, andpreferably prevents the abuse of the dosage form.

A bittering agent may be added to the formulation in an amount of lessthan about 50% by weight preferably less than about 10% by weight, mostpreferably less than about 5% by weight of the dosage form, and mostpreferably in an amount ranging from about 0.1 to 1.0 percent by weightof the dosage form depending on the particular bittering agent(s) used.A dosage form including a bittering agent preferably discouragesimproper usage of the tampered dosage form by imparting a disagreeabletaste or flavor to the tampered dosage form.

In certain embodiments of the present invention wherein the dosage formincludes an aversive agent comprising an irritant, various irritants canbe employed including, for example and without limitation capsaicin, acapsaicin analog with similar type properties as capsaicin, and thelike. Some capsaicin analogues or derivatives include for example andwithout limitation, resiniferatoxin, tinyatoxin, heptanoylisobutylamide,heptanoyl guaiacylamide, other isobutylamides or guaiacylamides,dihydrocapsaicin, homovanillyl octylester, nonanoyl vanillylamide, orother compounds of the class known as vanilloids. Resiniferatoxin isdescribed, for example, in U.S. Pat. No. 5,290,816 (Blumberg), issuedMar. 1, 1994. U.S. Pat. No. 4,812,446 (Brand), issued Mar. 14, 1989,describes capsaicin analogs and methods for their preparation. Further,U.S. Pat. No. 4,424,205 (LaHann et al.), issued Jan. 3, 1984, citeNewman, “Natural and Synthetic Pepper-Flavored Substances” published in1954 as listing pungency of capsaicin-like analogs. Ton et al., BritishJournal of Pharmacology, 10, pp. 175-182 (1955) discuss pharmacologicalactions of capsaicin and its analogs.

With the inclusion of an irritant (e.g., capsaicin) in the dosage form,when the dosage form is tampered with, the capsaicin imparts a burningor discomforting quality to the to the abuser to preferably discouragethe inhalation, injection, or oral administration of the tampered dosageform, and preferably to prevent the abuse of the dosage form. Suitablecapsaicin compositions include capsaicin (trans8-methyl-N-vanillyl-6-noneamide) or analogues thereof in a concentrationbetween about 0.00125% and 50% by weight, preferably between about 1 andabout 7.5% by weight, and most preferably, between about 1 and about 5%by weight.

In certain embodiments of the present invention wherein the dosage formincludes an aversive agent comprising a gelling agent, various gellingagents can be employed including, for example and without limitation,sugars or sugar derived alcohols, such as mannitol, sorbitol, and thelike, starch and starch derivatives, cellulose derivatives, such asmicrocrystalline cellulose, sodium caboxymethyl cellulose,methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, and hydroxypropyl methylcellulose, attapulgites, bentonites,dextrins, alginates, carrageenan, gum tragacant, gum acacia, guar gum,xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminumsilicate, the carbomers and carbopols, polyvinylpyrrolidone,polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicondioxide, surfactants, mixed surfactant/wetting agent systems,emulsifiers, other polymeric materials, and mixtures thereof, etc. Incertain preferred embodiments, the gelling agent is xanthan gum. Inother preferred embodiments, the gelling agent of the present inventionis pectin. The pectin or pectic substances useful for this inventioninclude not only purified or isolated pectates but also crude naturalpectin sources, such as apple, citrus or sugar beet residues which havebeen subjected, when necessary, to esterification or de-esterification,e.g., by alkali or enzymes. Preferably, the pectins used in thisinvention are derived from citrus fruits such as lime, lemon,grapefruit, and orange.

With the inclusion of a gelling agent in the dosage form, when thedosage form is tampered with, the gelling agent preferably imparts agel-like quality to the tampered dosage form which preferably spoils orhinders the pleasure of obtaining a rapid high from the tampered dosageform due to the gel like consistency in contact with the mucousmembrane, and in certain embodiments, prevents the abuse of the dosageform by minimizing absorption, e.g. in the nasal passages. A gellingagent may be added to the formulation in a ratio of gelling agent toopioid agonist of from about 1:40 to about 40:1 by weight, preferablyfrom about 1:1 to about 30:1 by weight, and more preferably from about2:1 to about 10:1 by weight of the opioid agonist.

In certain other embodiments, the dosage form forms a viscous gel afterthe dosage form is tampered with, dissolved in an aqueous liquid (fromabout 0.5 to about 10 ml and preferably from 1 to about 5 ml), causingthe resulting mixture to have a viscosity of at least about 10 cP. Mostpreferably, the resulting mixture will have a viscosity of at leastabout 60 cP.

In certain other embodiments, the dosage form forms a viscous gel afterthe dosage form is tampered with, dissolved in an aqueous liquid (fromabout 0.5 to about 10 ml and preferably from 1 to about 5 ml) and thenheated (e.g., greater than about 45° C.), causing the resulting mixtureto have a viscosity of at least about 10 cP. Most preferably, theresulting mixture will have a viscosity of at least about 60 cP.

In certain embodiments, the dosage form may include one or more of theaforementioned aversive agents. For safety reasons, the amount of thebittering agent, irritant, or gelling agent in the formulation of thepresent invention should not be toxic to humans.

Opioid antagonists useful in the present invention include, for exampleand without limitation, naltrexone, naloxone, nalmefene, nalide,nalmexone, nalorphine, nalorphine dinicotinate, cyclazocine,levallorphan, pharmaceutically acceptable salts thereof, and mixturesthereof. In certain preferred embodiments, the opioid antagonist isnaloxone or naltrexone. In certain embodiments, the amount of the opioidantagonist included in the dosage form, may be about 10 ng to 275 mg.

Naloxone is an opioid antagonist which is almost void of agonisteffects. Subcutaneous doses of up to 12 mg of naloxone produce nodiscernable subjective effects, and 24 mg naloxone causes only slightdrowsiness. Small doses (0.4-0.8 mg) of naloxone given intramuscularlyor intravenously in man prevent or promptly reverse the effects ofmorphine-like opioid agonist. One mg of naloxone intravenously has beenreported to completely block the effect of 25 mg of heroin. The effectsof naloxone are seen almost immediately after intravenousadministration. The drug is absorbed after oral administration, but hasbeen reported to be metabolized into an inactive form rapidly in itsfirst passage through the liver such that it has been reported to havesignificantly lower potency than as when parenterally administered. Oraldosages of more than 1 g have been reported to be almost completelymetabolized in less than 24 hours. It has been reported that 25% ofnaloxone administered sublingually is absorbed. Weinberg, et al.,Sublingual Absorption of selected Opioid Analgesics, Clin PharmacolTher. (1988); 44:335-340.

Other opioid antagonists, for example, cyclazocine and naltrexone, bothof which have cyclopropylmethyl substitutions on the nitrogen, retainmuch of their efficacy by the oral route and their durations of actionare much longer, approaching 24 hours after their oral administration.

In the treatment of patients previously addicted to opioids, naltrexonehas been used in large oral doses (over 100 mg) to prevent euphorigeniceffects of opioid agonists. Naltrexone has been reported to exert strongpreferential blocking action against mu over delta sites. Naltrexone isknown as a synthetic congener of oxymorphone with no opioid agonistproperties, and differs in structure from oxymorphone by the replacementof the methyl group located on the nitrogen atom of oxymorphone with acyclopropylmethyl group. The hydrochloride salt of naltrexone is solublein water up to about 100 mg/cc. The pharmacological and pharmacokineticproperties of naltrexone have been evaluated in multiple animal andclinical studies. See, e.g., Gonzalez J P, et al. Naltrexone: A reviewof its Pharmacodynamic and Pharmacokinetic Properties and TherapeuticEfficacy in the Management of Opioid Dependence. Drugs 1988; 35:192-213,hereby incorporated by reference. Following oral administration,naltrexone is rapidly absorbed (within 1 hour) and has an oralbioavailability ranging from 5-40%. Naltrexone's protein binding isapproximately 21% and the volume of distribution following single-doseadministration is 16.1 L/kg.

Naltrexone is commercially available in tablet form (Revia®, DuPont) forthe treatment of alcohol dependence and for the blockade of exogenouslyadministered opioids. See, e.g., Revia (naltrexone hydrochloridetablets). Physician's Desk Reference 51^(st) ed., Montvale, N.J.“Medical Economics” 1997; 51:90-959. A dosage of 50 mg Revia® blocks thepharmacological effects of 25 mg IV administered heroin for up to 24hours.

It is known that when coadministered with morphine, heroin or otheropioids on a chronic basis, naltrexone blocks the development ofphysical dependence to opioids. It is believed that the method by whichnaltrexone blocks the effects of heroin is by competitively binding atthe opioid receptors. Naltrexone has been used to treat narcoticaddiction by complete blockade of the effects of opioids. It has beenfound that the most successful use of naltrexone for a narcoticaddiction is with narcotic addicts having good prognosis, as part of acomprehensive occupational or rehabilitative program involvingbehavioral control or other compliance enhancing methods. For treatmentof narcotic dependence with naltrexone, it is desirable that the patientbe opioid-free for at least 7-10 days. The initial dosage of naltrexonefor such purposes has typically been about 25 mg, and if no withdrawalsigns occur, the dosage may be increased to 50 mg per day. A dailydosage of 50 mg is considered to produce adequate clinical blockade ofthe actions of parenterally administered opioids. Naltrexone has alsobeen used for the treatment of alcoholism as an adjunct with social andpsychotherapeutic methods.

In certain embodiments, the aversive agent and/or the opioid antagonistincluded in the dosage form may be in a substantially non-releasableform. Where the opioid antagonist is in a substantially non-releasableform, the substantially non-releasable form of the opioid antagonistcomprises an opioid antagonist that is formulated with one or morepharmaceutically acceptable hydrophobic materials, such that theantagonist is not released or substantially not released during itstransit through the gastrointestinal tract when administered orally asintended, without having been tampered with.

Additionally, in certain embodiments, wherein the aversive agent is in asubstantially non-releasable form, the substantially non-releasable formof the aversive agent comprises an aversive agent that is formulatedwith one or more pharmaceutically acceptable materials acceptablehydrophobic materials, such that the aversive agent is not released orsubstantially not released during its transit through thegastrointestinal tract when administered orally as intended, withouthaving been tampered with.

In certain embodiments of the present invention, the substantiallynon-releasable form of the opioid antagonist is vulnerable tomechanical, thermal and/or chemical tampering, e.g., tampering by meansof crushing, shearing, grinding, chewing and/or dissolution in a solventin combination with heating (e.g., greater than about 45° C.) of theoral dosage form. When the dosage form is tampered with, the integrityof the substantially non-releasable form of the opioid antagonist willbe compromised, and the opioid antagonist will be made available to bereleased. In certain embodiments, when the dosage form is chewed,crushed or dissolved and heated in a solvent, and administered orally,intranasally, parenterally or sublingually, the analgesic or euphoriceffect of the opioid is reduced or eliminated. In certain embodiments,the effect of the opioid agonist is at least partially blocked by theopioid antagonist. In certain other embodiments, the effect of theopioid agonist is substantially blocked by the opioid antagonist.

Additionally, the substantially non-releasable form of the aversiveagent is vulnerable to mechanical, thermal and/or chemical tampering,e.g., tampering by means of crushing, shearing, grinding, chewing and/ordissolution in a solvent in combination with heating (e.g., greater thanabout 45° C.) of the oral dosage form. When the dosage form is tamperedwith, the integrity of the substantially non-releasable form of theaversive agent will be compromised, and the aversive agent will be madeavailable to be released. In certain embodiments, when the dosage formis chewed, crushed or dissolved and heated in a solvent, the release ofthe aversive agent hinders, deters or prevents the administration of thetampered dosage form orally, intranasally, parenterally and/orsublingually.

In certain embodiments of the present invention, ratio of the opioidagonist to the substantially non-releasable form of an opioid antagonistin the oral dosage form is such that the effect of the opioid agonist isat least partially blocked when the dosage form is chewed, crushed ordissolved in a solvent and heated, and administered orally,intranasally, parenterally or sublingually. Since the oral dosage formof certain embodiments described herein, when administered properly asintended, would not substantially release the opioid antagonist and/orthe aversive agent, the amount of such antagonist and/or aversive agentmay be varied more widely than if the opioid antagonist and/or aversiveagent is available to be released into the gastrointestinal system uponoral administration. For safety reasons, the amount of the antagonistand/or aversive agent present in a substantially non-releasable formshould not be harmful to humans even if fully released. The ratio ofparticular opioid agonist to antagonist can be determined without undueexperimentation by one skilled in the art.

In certain embodiments of the present invention, the ratio of the opioidagonist and the opioid antagonist, present in a substantiallynon-releasable form, is about 1:1 to about 50:1 by weight, preferablyabout 1:1 to about 20:1 by weight. In certain preferred embodiments, theratio is about 1:1 to about 10:1 by weight. In a preferred embodiment ofthe invention, the opioid agonist comprises oxycodone or hydrocodone andis present in the amount of about 15-45 mg and the opioid antagonistcomprises naltrexone and is present in an amount of about 0.5 to about10 mg, preferably about 0.5 to about 5 mg.

In an alternative embodiment, the opioid antagonist of the presentinvention may be included in the dosage form, such that it isanalgesically effective when orally administered, but which uponparenteral administration, does not produce analgesia, euphoria orphysical dependence. In this particular embodiment, preferably theopioid antagonist is naloxone which is in an amount which is not orallyeffective, but is parenterally effective, as described in U.S. Pat. No.3,773,955, the disclosure of which is hereby incorporated by referencein its entirety. In this embodiment, the naloxone is released from thedosage form when orally administered, but does not abolish the oralactivity of the opioid analgesic included in the dosage form.

Alternatively, the opioid antagonist of the present invention isreleased from the dosage form upon oral administration and may beincluded in the dosage form in an amount as described in WO 99/32119,the disclosure of which is hereby incorporated by reference in itsentirety, (i) which does not cause a reduction in the level of analgesiaelicited from the dosage form upon oral administration to anon-therapeutic level and (ii) which provides at least a mildlynegative, “aversive” experience in physically dependent subjects (e.g.,precipitated abstinence syndrome) when the subjects attempt to take atleast twice the usually prescribed dose at a time (and often 2-3 timesthat dose or more), as compared to a comparable dose of the opioidwithout the opioid antagonist present. Preferably, the amount ofantagonist included in the oral dosage form is less positivelyreinforcing (e.g., less “liked”) to a non-physically dependent opioidaddict than a comparable oral dosage form without the antagonistincluded. Preferably, the formulation provides effective analgesia whenorally administered. In certain preferred embodiments, the oral dosageform comprises an orally therapeutically effective dose of an opioidagonist, and an opioid antagonist in a ratio that provides a combinationproduct which is analgesically effective when the combination isadministered orally, but which is aversive in physically dependent humansubjects when administered at the same dose or at a higher dose thansaid therapeutically effective dose.

Based on a preferred ratio of naltrexone in an amount from about 0.5 toabout 4 mg per 15 mg of hydrocodone as described in WO 99/32119, theapproximate ratio of naltrexone to 1 mg of certain opioids is set forthin Table A:

TABLE A Weight Ratio of Naltrexone per Dose Opioid Weight RatioNaltrexone per Opioid 1 mg Opioid Oxycodone 0.037 to 0.296 Codeine 0.005to 0.044 Hydrocodone 0.033 to 0.267 Hydromorphone 0.148 to 1.185Levorphanol 0.278 to 2.222 Meperidine 0.0037 to 0.0296 Methadone 0.056to 0.444 Morphine 0.018 to 0.148

Based on the more preferred ratio of about 0.75 mg to about 3 mgnaltrexone per 15 mg hydrocodone of naltrexone as described in WO99/32119, the approximate ratio of naltrexone to 1 mg of certain opioidsis set forth in Table B below:

TABLE B Weight Ratio of Naltrexone per Dose Opioid Opioid Weight RatioNaltrexone Oxycodone 0.056 to 0.222 Codeine 0.0083 to 0.033  Hydrocodone0.050 to 0.200 Hydromorphone 0.222 to 0.889 Levorphanol 0.417 to 1.667Meperidine 0.0056 to 0.022  Methadone 0.083 to 0.333 Morphine 0.028 to0.111

In certain embodiments, the present invention is directed in part to anoral dosage form comprising an orally analgesically effective amount ofan opioid agonist and an opioid antagonist in a ratios as describedabove along with one or more aversive agents as described herein.

In certain alternative embodiments, when the opioid antagonist isnaloxone, the opioid agonist and antagonist (e.g., naloxone) included inthe present dosage forms may be in preferred ratios as described in U.S.Pat. No. 4,457,933 to Gordon et al., the disclosure of which is herebyincorporated by reference in its entirety, such that both the oral andparenteral abuse potentials of the opioid agonist is diminished withoutappreciably affecting the oral analgetic activity of the opioid agonist.

In certain alternative embodiments, the opioid antagonist may beincluded in the dosage form in an amount such that the opioid antagonistattenuates side effects of the opioid agonist, said side effects beinganti-analgesia, hyperalgesia, hyperexcitability, physical dependence,tolerance, and combinations of any of the foregoing. For example, incertain preferred embodiments, the amount of the opioid antagonist isfrom about 100 to about 1000 fold less that the amount of the opioidagonist. Certain preferred amounts of opioid antagonist to agonist inaccordance with this embodiment are described, for example, in U.S. Pat.Nos. 5,472,943; 5,512,578; 5,580,876; 5,767,125; RE36,547; and 6,096,256all to Crain et al., the disclosures of which are herein incorporated byreference in their entireties.

All known combinations of releasable opioid antagonists with opioidagonists such as those described in U.S. Pat. No. 3,773,955 (Pachter, etal.); U.S. Pat. No. 3,493,657 (Lewenstein, et al.) U.S. Pat. No.4,457,933 (Gordon, et al.); U.S. Pat. No. 4,582,835 (Lewis) U.S. Pat.Nos. 5,512,578; 5,472,943; 5,580,876; and 5,767,125 (Crain) and U.S.Pat. Nos. 4,769,372 and 4,785,000 (Kreek) can be combined with theaversive agents disclosed herein and all of these references are herebyincorporated by reference.

All commercial products of opioid agonist and releasable antagonists canbe combined with an aversive agent disclosed herein. For example, TalwinNX can be formulated with an aversive agent, e.g., a bittering agent toreduce oral abuse as well as parenteral abuse of the opioid therein.

The opioid agonists useful in the present invention include, but are notlimited to, alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, desomorphine, dextromoramide, dezocine, diampromide,diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives,heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol,properidine, propoxyphene, sufentanil, tilidine, tramadol, mixtures ofany of the foregoing, salts of any of the foregoing, and the like. Incertain embodiments, the amount of the opioid agonist in the claimedopioid composition may be about 75 ng to about 750 mg.

In certain preferred embodiments, the opioid agonist is selected fromthe group consisting of hydrocodone, morphine, hydromorphone, oxycodone,codeine, levorphanol, meperidine, methadone, oxymorphone, buprenorphine,fentanyl and derivatives thereof, dipipanone, heroin, tramadol,etorphine, dihydroetorphine, butorphanol, levorphanol, or salts thereofor mixtures thereof. In certain preferred embodiments, the opioidagonist is oxycodone or hydrocodone.

In embodiments in which the opioid analgesic comprises hydrocodone,dosage forms may include analgesic doses from about 2 mg to about 50 mgof hydrocodone bitartrate. In embodiments in which the opioid analgesiccomprises hydromorphone the dosage form may include from about 2 mg toabout 64 mg hydromorphone hydrochloride. In embodiments in which theopioid analgesic comprises morphine, the dosage form may include fromabout 2.5 mg to about 800 mg morphine sulfate, by weight. In embodimentsin which the opioid analgesic comprises oxycodone, the dosage form mayinclude from about 2.5 mg to about 320 mg oxycodone hydrochloride. Thedosage form may contain more than one opioid analgesic to provide atherapeutic effect. Alternatively, the dosage form may contain molarequivalent amounts of other salts of the opioids useful in the presentinvention.

Although hydrocodone and oxycodone are effective in the management ofpain, there has been an increase in their abuse by individuals who arepsychologically dependent on opioids or who misuse opioids fornon-therapeutic reasons. Previous experience with other opioids hasdemonstrated a decreased abuse potential when opioids are administeredin combination with a narcotic antagonist especially in patients who areex-addicts. Weinhold L L, et al. Buprenorphine Alone and in Combinationwith Naltrexone in Non-Dependent Humans, Drug and Alcohol Dependence1992; 30:263-274; Mendelson J., et al., Buprenorphine and NaloxoneInteractions in Opiate-Dependent Volunteers, Clin Pharm Ther. 1996;60:105-114; both of which are hereby incorporated by reference. Thesecombinations, however, do not contain the opioid antagonist that is in asubstantially non-releasable form. Rather, the opioid antagonist isreleased in the gastrointestinal system when orally administered and ismade available for absorption, relying on the physiology of the host todifferentially metabolize the agonist and antagonist and negate theagonist effects.

Hydrocodone is a semisynthetic narcotic analgesic and antitussive withmultiple central nervous system and gastrointestinal actions.Chemically, hydrocodone is 4,5-epoxy-3-methoxy-17-methylmorphinan-6-one,and is also known as dihydrocodeinone. Like other opioids, hydrocodonemay be habit forming and may produce drug dependence of the morphinetype. In excess doses hydrocodone, like other opium derivatives, willdepress respiration.

Oral hydrocodone is also available in Europe (Belgium, Germany, Greece,Italy, Luxembourg, Norway and Switzerland) as an antitussive agent. Aparenteral formulation is also available in Germany as an antitussiveagent. For use as an analgesic, hydrocodone bitartrate is commerciallyavailable in the United States only as a fixed combination withnon-opiate drugs (i.e., ibuprofen, acetaminophen, aspirin, etc.) forrelief of moderate or moderately severe pain.

A common dosage form of hydrocodone is in combination withacetaminophen, and is commercially available, e.g., as Lortab® in theU.S. from UCB Pharma, Inc. as 2.5/500 mg, 5/500 mg, 7.5/500 mg and10/500 mg hydrocodone/acetaminophen tablets. Tablets are also availablein the ratio of 7.5 mg hydrocodone bitartrate and 650 mg acetaminophen;and 7.5 mg hydrocodone bitartrate and 750 mg acetaminophen. Hydrocodonein combination with aspirin is given in an oral dosage form to adultsgenerally in 1-2 tablets every 4-6 hours as needed to alleviate pain.The tablet form is 5 mg hydrocodone bitartrate and 224 mg aspirin with32 mg caffeine; or 5 mg hydrocodone bitartrate and 500 mg aspirin. Arelatively new formulation comprises hydrocodone bitartrate andibuprofen. Vicoprofen®, commercially available in the U.S. from KnollLaboratories, is a tablet containing 7.5 mg hydrocodone bitartrate and200 mg ibuprofen. The present invention is contemplated to encompass allsuch formulations, with the inclusion of the opioid antagonist particlescoated with a coating that renders the antagonist substantiallynon-releasable.

Oxycodone, chemically known as4,5-expoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one, is an opioidagonist whose principal therapeutic action is analgesia. Othertherapeutic effects of oxycodone include anxiolysis, euphoria andfeelings of relaxation. The precise mechanism of its analgesic action isnot known, but specific CNS opioid receptors for endogenous compoundswith opioid-like activity have been identified throughout the brain andspinal cord and play a role in the analgesic effects of this drug.

Oxycodone is commercially available in the United States, e.g., asOxycontin® from Purdue Pharma L.P. as controlled-release tablets fororal administration containing 10 mg, 20 mg, 40 mg or 80 mg oxycodonehydrochloride, and as OxyIR™, also from Purdue Pharma L.P., asimmediate-release capsules containing 5 mg oxycodone hydrochloride. Thepresent invention is contemplated to encompass all such formulations,with the inclusion of an opioid antagonist and one or more aversiveagents.

Preparation of Aversive Agent in a Substantially Non-Releasable Form

In certain embodiments of the present invention, an aversive agent in asubstantially non-releasable form may be prepared by combining theaversive agent with one or more of a pharmaceutically acceptablehydrophobic material. For example, aversive agent particles may becoated with coating that substantially prevents the release of theaversive agent, the coating comprising the hydrophobic materials(s).Another example would be an aversive agent that is dispersed in a matrixthat renders the aversive agent substantially non-releasable, the matrixcomprising the hydrophobic materials(s). In certain embodiments, thepharmaceutically acceptable hydrophobic material comprises a cellulosepolymer selected from the group consisting of ethylcellulose, celluloseacetate, cellulose propionate (lower, medium or higher molecularweight), cellulose acetate propionate, cellulose acetate butyrate,cellulose acetate phthalate and cellulose triacetate. An example ofethylcellulose is one that has an ethoxy content of 44 to 55%.Ethylcellulose may be used in the form of an alcoholic solution. Incertain other embodiments, the hydrophobic material comprises polylacticacid, polyglycolic acid or a co-polymer of the polylactic andpolyglycolic acid.

In certain embodiments, the hydrophobic material may comprise acellulose polymer selected from the group consisting of cellulose ether,cellulose ester, cellulose ester ether, and cellulose. The cellulosicpolymers have a degree of substitution, D.S., on the anhydroglucoseunit, from greater than zero and up to 3 inclusive. By degree ofsubstitution is meant the average number of hydroxyl groups present onthe anhydroglucose unit comprising the cellulose polymer that arereplaced by a substituting group. Representative materials include apolymer selected from the group consisting of cellulose acylate,cellulose diacylate, cellulose triacylate, cellulose acetate, cellulosediacetate, cellulose triacetate, mono, di, and iricellulose alkanylates,mono, di, and tricellulose aroylates, and mono, di, and tricellulosealkenylates. Exemplary polymers include cellulose acetate having a D.S,and an acetyl content up to 21%; cellulose acetate having an acetylcontent up to 32 to 39.8%; cellulose acetate having a D.S. of 1 to 2 andan acetyl content of 21 to 35%; cellulose acetate having a D.S. of 2 to3 and an acetyl content of 35 to 44.8%.

More specific cellulosic polymers include cellulose propionate having aD.S. of 1.8 and a propyl content of 39.2 to 45 and a hydroxyl content of2.8 to 5.4%; cellulose acetate butyrate having a D.S. of 1.8, an acetylcontent of 13 to 15% and a butyryl content of 34 to 39%; celluloseacetate butyrate having an acetyl content of 2 to 29%, a butyryl contentof 17 to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacylatehaving D.S. of 2.9 to 3 such as cellulose triacetate, cellulosetrivalerate, cellulose trilaurate, cellulose tripalmitate, cellulosetrisuccinate, and cellulose trioctanoate; cellulose diacylates having aD.S. of 2.2 to 2.6 such as cellulose disuccinate, cellulose dipalmitate,cellulose dioctanoate, cellulose dipentanoate, and coesters of cellulosesuch as cellulose acetate butyrate, cellulose acetate octanoate butyrateand cellulose acetate propionate.

Additional cellulose polymers useful for preparing an aversive agent ina substantially non-releasable form include acetaldehyde dimethylcellulose acetate, cellulose acetate ethylcarbamate, cellulose acetatemethylcarbamate, and cellulose acetate dimethylaminocellulose acetate.

Acrylic polymers useful for preparation of the aversive agent in asubstantially non-releasable form include, but are not limited to,acrylic resins comprising copolymers synthesized from acrylic andmethacrylic acid esters (e.g., the copolymer of acrylic acid lower alkylester and methacrylic acid lower alkyl ester) containing about 0.02 to0.03 mole of a tri (lower alkyl) ammonium group per mole of the acrylicand methacrylic monomers used. An example of a suitable acrylic resin isa polymer manufactured by Rohm Pharma GmbH and sold under the Eudragit®RS trademark. Eudragit RS30D is preferred. Eudragit® RS is a waterinsoluble copolymer of ethyl acrylate (EA), methyl methacrylate (MM) andtrimethylammoniumethyl methacrylate chloride (TAM) in which the molarratio of TAM to the remaining components (EA and MM) is 1:40. Acrylicresins such as Eudragit® RS may be used in the form of an aqueoussuspension.

In certain embodiments of the invention, the acrylic polymer may beselected from the group consisting of acrylic acid and methacrylic acidcopolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates,cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamide copolymer, poly(methyl methacrylate),polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), andglycidyl methacrylate co-polymers.

When the aversive agent in a substantially non-releasable form comprisesaversive agent particles coated with a coating that renders the aversiveagent substantially non-releasable, and when a cellulose polymer or anacrylic polymer is used for preparation of the coating composition,suitable plasticizers, e.g., acetyl triethyl citrate and/or acetyltributyl citrate may also be admixed with the polymer. The coating mayalso contain additives such as coloring agents, talc and/or magnesiumstearate, which are well known in the coating art.

The coating composition may be applied onto the aversive agent particlesby spraying it onto the particles using any suitable spray equipmentknown in the art. For example, a Wuster fluidized-bed system may be usedin which an air jet, injected from underneath, fluidizes the coatedmaterial and effects drying while the insoluble polymer coating issprayed on. The thickness of the coating will depend on thecharacteristics of the particular coating composition being used.However, it is well within the ability of one skilled in the art todetermine by routine experimentation the optimum thickness of aparticular coating required for a particular dosage form of the presentinvention.

The pharmaceutically acceptable hydrophobic material useful forpreparing an aversive agent in a substantially non-releasable formincludes a biodegradable polymer comprising a poly(lactic/glycolic acid)(“PLGA”), a polylactide, a polyglycolide, a polyanhydride, apolyorthoester, polycaprolactones, polyphosphazenes, polysaccharides,proteinaceous polymers, polyesthers, polydioxanone, polygluconate,polylactic-acid-polyethylene oxide copolymers, poly(hydroxybutyrate),polyphosphoesther or mixtures or blends of any of these.

In certain embodiments, biodegradable polymer comprises apoly(lactic/glycolic acid), a copolymer of lactic and glycolic acid,having molecular weight of about 2,000 to about 500,000 daltons. Theratio of lactic acid to glycolic acid is from about 100:0 to about25:75, with the ratio of lactic acid to glycolic acid of 65:35 beingpreferred.

Poly(lactic/glycolic acid) may be prepared by the procedure set forth inU.S. Pat. No. 4,293,539 (Ludwig et al.), the disclosure of which ishereby incorporated by reference in its entirety. In brief, Ludwigprepares the copolymer by condensation of lactic acid and glycolic acidin the presence of a readily removable polymerization catalyst (e.g., astrong acid ion-exchange resin such as Dowex HCR-W2-H). The amount ofcatalyst is not critical to the polymerization, but typically is fromabout 0.01 to about 20 parts by weight relative to the total weight ofcombined lactic acid and glycolic acid. The polymerization reaction maybe conducted without solvents at a temperature from about 100° C. toabout 250° C. for about 48 to about 96 hours, preferably under a reducedpressure to facilitate removal of water and by-products.Poly(lactic/glycolic acid) is then recovered by filtering the moltenreaction mixture in an organic solvent such as dichloromethane oracetone and then filtering to remove the catalyst.

Once the aversive agent in a substantially non-releasable form isprepared, it may be combined with an opioid agonist and the opioidantagonist (which may also be in a substantially non-releasable form asdescribed herein), along with conventional excipients known in the art,to prepare the oral dosage form of the present invention. It iscontemplated that a bittering agent or capsaicin would be the mostlikely aversive agents to be included in a sequestered formulation. Thepolymers and other ingredients above may also be utilized to formulatethe aversive agents to slow release or delay release as disclosed above.

In certain preferred embodiments of the invention, the oral dosage formis a capsule or a tablet. When being formulated as a tablet, theaversive agent and opioid agonist and opioid antagonist may be combinedwith one or more inert, non-toxic pharmaceutical excipients which aresuitable for the manufacture of tablets. Such excipients include, forexample, an inert diluent such as lactose; granulating anddisintegrating agents such as cornstarch; binding agents such as starch;and lubricating agents such as magnesium stearate.

The oral dosage form of the present invention may be formulated toprovide immediate release of the opioid agonist contained therein. Inother embodiments of the invention, however, the oral dosage formprovides sustained-release of the opioid agonist.

In certain embodiments, the oral dosage forms providing sustainedrelease of the opioid agonist may be prepared by admixing the aversiveagent in a substantially non-releasable form with the opioid agonist andthe opioid antagonist and desirable pharmaceutical excipients to providea tablet, and then coating the tablet with a sustained-release tabletcoating.

In certain embodiments of the invention, sustained release opioidagonist tablets may be prepared by admixing the substantiallynon-releasable form of an aversive agent with an aversive agent in amatrix that provides the tablets with sustained-releasing properties.

Dosage Forms

The opioid analgesic/opioid antagonist formulation in combination withone or more aversive agents can be formulated as an immediate releaseformulation or controlled release oral formulation in any suitabletablet, coated tablet or multiparticulate formulation known to thoseskilled in the art. The controlled release dosage form may include acontrolled release material which is incorporated into a matrix alongwith the opioid analgesic and the opioid antagonist. In addition, theaversive agent may be separate from the matrix, or incorporated into thematrix.

The controlled release dosage form may optionally comprise particlescontaining or comprising the opioid analgesic, wherein the particleshave diameter from about 0.1 mm to about 2.5 mm, preferably from about0.5 mm to about 2 mm. The opioid antagonist may be incorporated intothese particles, or may be incorporated into a tablet or capsulecontaining these particles. Additionally, the aversive agent may beincorporated into these particles, or may be incorporated into a tabletor capsule containing these particles. Preferably, the particles arefilm coated with a material that permits release of the opioid analgesicat a controlled rate in an environment of use. The film coat is chosenso as to achieve, in combination with the other stated properties, adesired in-vitro release rate. The controlled release coatingformulations of the present invention should be capable of producing astrong, continuous film that is smooth and elegant, capable ofsupporting pigments and other coating additives, non-toxic, inert, andtack-free.

In certain embodiments, the dosage forms of the present inventioncomprise normal release matrixes containing the opioid analgesic, opioidantagonist, and the aversive agent.

Coated Beads

In certain embodiments of the present invention a hydrophobic materialis used to coat inert pharmaceutical beads such as nu pariel 18/20 beadscomprising an opioid analgesic, and a plurality of the resultant solidcontrolled release beads may thereafter be placed in a gelatin capsulein an amount sufficient to provide an effective controlled release dosewhen ingested and contacted by an environmental fluid, e.g., gastricfluid or dissolution media. The heads comprising the opioid analgesicmay further comprise the opioid antagonist and/or one or more aversiveagents, or the opioid antagonist and or one or more aversive agents maybe prepared as separate beads and then combined in a dosage formincluding the controlled release beads comprising an opioid analgesic,or the opioid antagonist and/or one or more aversive agents may be mixedin the dosage form with the controlled release beads comprising theopioid analgesic. In preferred embodiments where the opioid analgesicand the aversive agent are mixed in a capsule as different beads, thebeads have an exact or similar appearance in order to deter an abuserfrom manually separating the beads prior to abuse in order to avoid theaversive substance. In tablet dosage forms, the aversive agent ispreferably not included as a distinct layer which can be easier toseparate from the active agent, although the present invention doesencompass these embodiments.

The controlled release bead formulations of the present invention slowlyrelease the opioid analgesic. e.g., when ingested and exposed to gastricfluids, and then to intestinal fluids. The controlled release profile ofthe formulations of the invention can be altered, for example, byvarying the amount of overcoating with the hydrophobic material,altering the manner in which a plasticizer is added to the hydrophobicmaterial, by varying the amount of plasticizer relative to hydrophobicmaterial, by the inclusion of additional ingredients or excipients, byaltering the method of manufacture, etc. The dissolution profile of theultimate product may also be modified, for example, by increasing ordecreasing the thickness of the retardant coating.

Spheroids or beads coated with an opioid analgesic are prepared, e.g.,by dissolving the opioid analgesic in water and then spraying thesolution onto a substrate, for example, nu pariel 18/20 beads, using aWuster insert. Thereafter, the opioid antagonist and/or aversive agentis optionally added to the beads prior to coating. Optionally,additional ingredients are also added prior to coating the beads. Forexample, a product which includes hydroxypropylmethylcellulose, etc.(e.g., Opadry®, commercially available from Colorcon, Inc.) may be addedto the solution and the solution mixed (e.g., for about 1 hour) prior toapplication of the same onto the beads. The resultant coated substrate,in this example beads, may then be optionally overcoated with a barrieragent, to separate the opioid analgesic from the hydrophobic controlledrelease coating. An example of a suitable barrier agent is one whichcomprises hydroxypropylmethylcellulose. However, any film-former knownin the art may be used. It is preferred that the barrier agent does notaffect the dissolution rate of the final product.

The beads may then be overcoated with an aqueous dispersion of thehydrophobic material. The aqueous dispersion of hydrophobic materialpreferably further includes an effective amount of plasticizer, e.g.triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose,such as Aquacoat® or Surelease®, may be used. If Surelease® is used, itis not necessary to separately add a plasticizer. Alternatively,pre-formulated aqueous dispersions of acrylic polymers such as Eudragit®can be used.

Plasticized hydrophobic material may be applied onto the substratecomprising the opioid analgesic by spraying using any suitable sprayequipment known in the art. In a preferred method, a Wursterfluidized-bed system is used in which an air jet, injected fromunderneath, fluidizes the core material and effects drying while theacrylic polymer coating is sprayed on. A sufficient amount of thehydrophobic material to obtain a predetermined controlled release ofsaid opioid analgesic when the coated substrate is exposed to aqueoussolutions, e.g. gastric fluid, is preferably applied, taking intoaccount the physical characteristics of the opioid analgesic, the mannerof incorporation of the plasticizer, etc. After coating with thehydrophobic material, a further overcoat of a film-former, such asOpadry®, is optionally applied to the beads. This overcoat is provided,if at all, in order to substantially reduce agglomeration of the beads.

The release of the opioid analgesic from the controlled releaseformulation of the present invention can be further influenced, i.e.,adjusted to a desired rate, by the addition of one or morerelease-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic material to water solublematerial is determined by, among other factors, the release raterequired and the solubility characteristics of the materials selected.

The release-modifying agents which function as pore-formers may beorganic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

The controlled release coatings of the present invention can alsoinclude erosion-promoting agents such as starch and gums.

The controlled release coatings of the present invention can alsoinclude materials useful for making microporous lamina in theenvironment of use, such as polycarbonates comprised of linearpolyesters of carbonic acid in which carbonate groups reoccur in thepolymer chain.

The release-modifying agent may also comprise a semi-permeable polymer.

In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

The controlled release coatings of the present invention may alsoinclude an exit means comprising at least one passageway, orifice, orthe like. The passageway may be formed by such methods as thosedisclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and4,088,864. The passageway can have any shape such as round, triangular,square, elliptical, irregular, etc.

Matrix Formulations

In certain embodiments of the present invention, the sustained releaseformulation is achieved via a matrix optionally having a controlledrelease coating as set forth herein. The present invention may alsoutilize a sustained release matrix that affords in-vitro dissolutionrates of the opioid analgesic and or antagonist within desired rangesand releases the opioid analgesic and/or antagonist in a pH-dependent orpH-independent manner.

A non-limiting list of suitable sustained-release materials which may beincluded in a sustained-release matrix according to the inventionincludes hydrophilic and/or hydrophobic materials, such as gums,cellulose ethers, acrylic resins, protein derived materials, waxes,shellac, and oils such as hydrogenated castor oil and hydrogenatedvegetable oil. However, any pharmaceutically acceptable hydrophobic orhydrophilic sustained-release material which is capable of impartingsustained-release of the opioid analgesic may be used in accordance withthe present invention. Preferred sustained-release polymers includealkylcelluloses such as ethylcellulose, acrylic and methacrylic acidpolymers and copolymers; and cellulose ethers, especiallyhydroxyalkylcelluloses (especially hydroxypropylmethylcellulose) andcarboxyalkylcelluloses. Preferred acrylic and methacrylic acid polymersand copolymers include methyl methacrylate, methyl methacrylatecopolymers, ethoxyethyl methacrylates, ethyl acrylate, trimethylammonioethyl methacrylate, cyanoethyl methacrylate, aminoalkylmethacrylate copolymer, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamine copolymer, poly(methylmethacrylate),poly(methacrylicacid) (anhydride), polymethacrylate, polyacrylamide,poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.Certain preferred embodiments utilize mixtures of any of the foregoingsustained-release materials in the matrix of the invention.

The matrix also may include a binder. In such embodiments, the binderpreferably contributes to the sustained-release of the oxycodone orpharmaceutically acceptable salt thereof from the sustained-releasematrix.

If an additional hydrophobic binder material is included, it ispreferably selected from natural and synthetic waxes, fatty acids, fattyalcohols, and mixtures of the same. Examples include beeswax, carnaubawax, stearic acid and stearyl alcohol. This list is not meant to beexclusive. In certain preferred embodiments, a combination of two ormore hydrophobic binder materials are included in the matrixformulations.

Preferred hydrophobic binder materials which may be used in accordancewith the present invention include digestible, long chain (C₈-C₅₀,especially C₁₂-C₄₀), substituted or unsubstituted hydrocarbons, such asfatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral andvegetable oils, natural and synthetic waxes and polyalkylene glycols.Hydrocarbons having a melting point of between 25° and 90° C. arepreferred. Of the long-chain hydrocarbon binder materials, fatty(aliphatic) alcohols are preferred in certain embodiments. The oraldosage form may contain up to 80% (by weight) of at least onedigestible, long chain hydrocarbon.

In certain embodiments, the hydrophobic binder material may comprisenatural or synthetic waxes, fatty alcohols (such as lauryl, myristyl,stearyl, cetyl or preferably cetostearyl alcohol), fatty acids,including but not limited to fatty acid esters, fatty acid glycerides(mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons,normal waxes, stearic acid, stearyl alcohol and hydrophobic andhydrophilic materials having hydrocarbon backbones. Suitable waxesinclude, for example, beeswax, glycowax, castor wax and carnauba wax.For purposes of the present invention, a wax-like substance is definedas any material which is normally solid at room temperature and has amelting point of from about 30 to about 100° C. In certain preferredembodiments, the dosage form comprises a sustained release matrixcomprising an opioid analgesic; opioid antagonist; one or more aversiveagents; and at least one water soluble hydroxyalkyl cellulose, at leastone C₁₂-C₃₆, preferably C₁₄-C₂₂, aliphatic alcohol and, optionally, atleast one polyalkylene glycol. The hydroxyalkyl cellulose is preferablya hydroxy (C₁ to C₆) alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose.The amount of the at least one hydroxyalkyl cellulose in the presentoral dosage form may be determined, inter alia, by the precise rate ofopioid analgesic release required. The aliphatic alcohol may be, forexample, lauryl alcohol, myristyl alcohol or stearyl alcohol. Inparticularly preferred embodiments of the present oral dosage form,however, the at least one aliphatic alcohol is cetyl alcohol orcetostearyl alcohol. The amount of the aliphatic alcohol in the presentoral dosage form may be determined, as above, by the precise rate ofopioid analgesic release required. It may also depend on whether atleast one polyalkylene glycol is present in or absent from the oraldosage form. In the absence of at least one polyalkylene glycol, theoral dosage form preferably contains between about 20% and about 50% (bywt) of the aliphatic alcohol. When a polyalkylene glycol is present inthe oral dosage form, then the combined weight of the aliphatic alcoholand the polyalkylene glycol preferably constitutes between about 20% andabout 50% (by wt) of the total dosage form.

In one preferred embodiment, the ratio of, e.g., the at least onehydroxyalkyl cellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a considerable extent, therelease rate of the opioid analgesic from the formulation. In certainembodiments, a ratio of the hydroxyalkyl cellulose to the aliphaticalcohol/polyalkylene glycol of between 1:1 and 1:4 is preferred, with aratio of between 1:2 and 1:3 being particularly preferred.

In certain embodiments, the polyalkylene glycol may be, for example,polypropylene glycol, or polyethylene glycol which is preferred. Theaverage molecular weight of the at least one polyalkylene glycol ispreferably between 1,000 and 15,000, especially between 1,500 and12,000.

Another suitable sustained-release matrix comprises an alkylcellulose(especially ethylcellulose), a C₁₂ to C₃₆ aliphatic alcohol and,optionally, a polyalkylene glycol.

In addition to the above ingredients, a sustained-release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids and glidants that are conventionalin the pharmaceutical art.

In order to facilitate the preparation of a solid, sustained-releaseoral dosage form according to this invention there is provided, in afurther aspect of the present invention, a process for the preparationof a solid, sustained-release oral dosage form according to the presentinvention comprising incorporating an opioid analgesic in asustained-release matrix. Incorporation in the matrix may be effected,for example, by:

(a) forming granules comprising at least one hydrophobic and/orhydrophilic material as set forth above (e.g., a water solublehydroxyalkyl cellulose) together with the opioid analgesic, opioidantagonist, and at least one aversive agent;

(b) mixing the at least one hydrophobic and/or hydrophilicmaterial-containing granules with at least one C₁₂-C₃₆ aliphaticalcohol, and

(c) optionally, compressing and shaping the granules.

The granules may be formed by any of the procedures well-known to thoseskilled in the art of pharmaceutical formulation. For example, in onepreferred method, the granules may be formed by wet granulating thehydroxyalkyl cellulose, opioid analgesic, opioid antagonist, and one ormore aversive agents with water. In a pr ticularly preferred embodimentof this process, the amount of water added during the wet granulationstep is preferably between 1.5 and 5 times, especially between 1.75 and3.5 times, the dry weight of the opioid analgesic. Optionally, theopioid analgesic, opioid antagonist, and/or the one or more aversiveagents are added extragranularly.

A sustained-release matrix can also be prepared by, e.g.,melt-granulation or melt-extrusion techniques. Generally,melt-granulation techniques involve melting a normally solid hydrophobicbinder material, e.g., a wax, and incorporating a powdered drug therein.To obtain a sustained release dosage form, it may be necessary toincorporate a hydrophobic sustained-release material, e.g.ethylcellulose or a water-insoluble acrylic polymer, into the molten waxhydrophobic binder material. Examples of sustained-release formulationsprepared via melt-granulation techniques are found, e.g., in U.S. Pat.No. 4,861,598.

The additional hydrophobic binder material may comprise one or morewater-insoluble wax-like thermoplastic substances possibly mixed withone or more wax-like thermoplastic substances being less hydrophobicthan said one or more water-insoluble wax-like substances. In order toachieve sustained release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like binder substances may be those with awater-solubility that is lower than about 1:5,000 (w/w).

The preparation of a suitable melt-extruded matrix according to thepresent invention may, for example, include the steps of blending theopioid analgesic, opioid antagonist, and at least one aversive agent,together with a sustained release material and preferably a bindermaterial to obtain a homogeneous mixture. The homogeneous mixture isthen heated to a temperature sufficient to at least soften the mixturesufficiently to extrude the same. The resulting homogeneous mixture isthen extruded, e.g., using a twin-screw extruder, to form strands. Theextrudate is preferably cooled and cut into multiparticles by any meansknown in the art. The matrix multiparticulates are then divided intounit doses. The extrudate preferably has a diameter of from about 0.1 toabout 5 mm and provides sustained release of the oxycodone orpharmaceutically acceptable salt thereof for a time period of at leastabout 24 hours.

An optional process for preparing the melt extruded formulations of thepresent invention includes directly metering into an extruder ahydrophobic sustained release material, the opioid analgesic, opioidantagonist, one or more aversive agents, and an optional bindermaterial; heating the homogenous mixture; extruding the homogenousmixture to thereby form strands; cooling the strands containing thehomogeneous mixture; cutting the strands into matrix multiparticulateshaving a size from about 0.1 mm to about 12 mm; and dividing saidparticles into unit doses. In this aspect of the invention, a relativelycontinuous manufacturing procedure is realized.

Optionally, the opioid antagonist and/or the one or more aversive agentsmay be prepared as separate multiparticulates (without the opioidagonist) and thereafter the multiparticulates may be combined withmultiparticulates comprising opioid analgesic (without the antagonistand/or the one or more aversive agents) in a dosage form.

Plasticizers, such as those described above, may be included inmelt-extruded matrices. The plasticizer is preferably included as fromabout 0.1 to about 30% by weight of the matrix. Other pharmaceuticalexcipients, e.g., talc, mono or poly saccharides, lubricants and thelike may be included in the sustained release matrices of the presentinvention as desired. The amounts included will depend upon the desiredcharacteristic to be achieved.

The diameter of the extruder aperture or exit port can be adjusted tovary the thickness of the extruded strands. Furthermore, the exit partof the extruder need not be round; it can be oblong, rectangular, etc.The exiting strands can be reduced to particles using a hot wire cutter,guillotine, etc.

A melt extruded matrix multiparticulate system can be, for example, inthe form of granules, spheroids or pellets depending upon the extruderexit orifice. For purposes of the present invention, the terms“melt-extruded matrix multiparticulate(s)” and “melt-extruded matrixmultiparticulate system(s)” and “melt-extruded matrix particles” shallrefer to a plurality of units, preferably within a range of similar sizeand/or shape and containing one or more active agents and one or moreexcipients, preferably including a hydrophobic sustained releasematerial as described herein. Preferably the melt-extruded matrixmultiparticulates will be of a range of from about 0.1 to about 12 mm inlength and have a diameter of from about 0.1 to about 5 mm. In addition,it is to be understood that the melt-extruded matrix multiparticulatescan be any geometrical shape within this size range. In certainembodiments, the extrudate may simply be cut into desired lengths anddivided into unit doses of the therapeutically active agent without theneed of a spheronization step.

In one preferred embodiment, oral dosage forms are prepared that includean effective amount of melt-extruded matrix multiparticulates within acapsule. For example, a plurality of the melt-extruded matrixmultiparticulates may be placed in a gelatin capsule in an amountsufficient to provide an effective sustained release dose when ingestedand contacted by gastrointestinal fluid.

In another embodiment, a suitable amount of the multiparticulateextrudate is compressed into an oral tablet using conventional tabletingequipment using standard techniques. Techniques and compositions formaking tablets (compressed and molded), capsules (hard and soft gelatin)and pills are also described in Remington's Pharmaceutical Sciences,(Arthur Osol, editor), 1553-1593 (1980).

In yet another preferred embodiment, the extrudate can be shaped intotablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et. al.).

Optionally, the sustained-release matrix multiparticulate systems,tablets, or capsules can be coated with a sustained release coating suchas the sustained release coatings described herein. Such coatingspreferably include a sufficient amount of hydrophobic and/or hydrophilicsustained-release material to obtain a weight gain level from about 2 toabout 25 percent, although the overcoat may be greater depending upon,e.g., the desired release rate. The coating can optionally contain oneor more of the aversive agents. In such embodiments, an optional secondovercoat can be applied as to minimize the perception of the aversiveagent when a dosage form of the present inventions administered intact.

The dosage forms of the present invention may further includecombinations of melt-extruded matrix multiparticulates containing anopioid analgesic; an opioid antagonist; one or more aversive agents; ormixtures thereof. Furthermore, the dosage foam can also include anamount of an immediate release opioid analgesic for prompt therapeuticeffect. The immediate release opioid analgesic may be incorporated,e.g., as separate multiparticulates within a gelatin capsule, or may becoated on the surface of, e.g., melt extruded matrix multiparticulates.

The sustained-release profile of the melt-extruded formulations of theinvention can be altered, for example, by varying the amount ofsustained-release material, by varying the amount of plasticizerrelative to other matrix constituents, by varying the amount ofhydrophobic material, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc.

In other embodiments of the invention, melt-extruded formulations areprepared without the inclusion of the opioid analgesic; opioidantagonist; one or more aversive agents; or mixtures thereof; which isadded thereafter to the extrudate. Such formulations typically will havethe opioid analgesic; opioid antagonist; one or more aversive agents; ormixtures thereof blended together with the extruded matrix material, andthen the mixture would be tableted in order to provide a slow releaseformulation. Such formulations may be advantageous, for example, whenthe opioid analgesic; opioid antagonist; one or more aversive agents; ormixtures thereof included in the formulation is sensitive totemperatures needed for softening the hydrophobic material and/or theretardant material.

Typical melt-extrusion production systems suitable for use in accordancewith the present invention include a suitable extruder drive motorhaving variable speed and constant torque control, start-stop controls,and a meter. In addition, the production system will include atemperature control console which includes temperature sensors, coolingmeans and temperature indicators throughout the length of the extruder.In addition, the production system will include an extruder such as atwin-screw extruder which consists of two counter-rotating intermeshingscrews enclosed within a cylinder or barrel having an aperture or die atthe exit thereof. The feed materials enter through a feed hopper and aremoved through the barrel by the screws and are forced through the dieinto strands which are thereafter conveyed such as by a continuousmovable belt to allow for cooling and being directed to a pelletizer orother suitable device to render the extruded ropes into the matrixmultiparticulate system. The pelletizer can consist of rollers, fixedknife, rotating cutter and the like. Suitable instruments and systemsare available from distributors such as C.W. Brabender Instruments, Inc.of South Hackensack, N.J. Other suitable apparatus will be apparent tothose of ordinary skill in the art.

A further aspect of the invention is related to the preparation ofmelt-extruded matrix multiparticulates as set forth above in a mannerwhich controls the amount of air included in the extruded product. Bycontrolling the amount of air included in the extrudate, the releaserate of the opioid analgesic, opioid antagonist, one or more aversiveagents, or mixtures thereof may be altered.

Thus, in a further aspect of the invention, the melt-extruded product isprepared in a manner which substantially excludes air during theextrusion phase of the process. This may be accomplished, for example,by using a Leistritz extruder having a vacuum attachment. The extrudedmatrix multiparticulates prepared according to the invention using theLeistritz extruder under vacuum provides a melt-extruded product havingdifferent physical characteristics. In particular, the extrudate issubstantially non-porous when magnified, e.g., using a scanning electronmicroscope which provides an SEM (scanning electron micrograph). Suchsubstantially non-porous formulations may provide a faster release ofthe therapeutically active agent, relative to the same formulationprepared without vacuum. SEMs of the matrix multiparticulates preparedusing an extruder under vacuum appear very smooth, and themultiparticulates tend to be more robust than those multiparticulatesprepared without vacuum. It has been observed that in at least certainformulations, the use of extrusion under vacuum provides an extrudedmatrix multiparticulate product which is more pH-dependent than itscounterpart formulation prepared without vacuum.

Alternatively, the melt-extruded product is prepared using aWemer-Pfleiderer twin screw extruder.

In certain embodiments, a spheronizing agent is added to a granulate ormatrix multiparticulate and then spheronized to produce sustainedrelease spheroids. The spheroids are then optionally overcoated with asustained release coating by methods such as those described above.

Spheronizing agents which may be used to prepare the matrixmultiparticulate formulations of the present invention include anyart-known spheronizing agent. Cellulose derivatives are preferred, andmicrocrystalline cellulose is especially preferred. A suitablemicrocrystalline cellulose is, for example, the material sold as AvicelPH 101 (TradeMark, FMC Corporation). The spheronizing agent ispreferably included as about 1 to about 99% of the matrixmultiparticulate by weight.

In certain embodiments, in addition to the opioid analgesic, opioidantagonist, one or more aversive agents, and spheronizing agent, thespheroids may also contain a binder. Suitable binders, such as lowviscosity, water soluble polymers, will be well known to those skilledin the pharmaceutical art. However, water soluble hydroxy lower alkylcellulose, such as hydroxy propyl cellulose, are preferred. Additionally(or alternatively) the spheroids may contain a water insoluble polymer,especially an acrylic polymer, an acrylic copolymer, such as amethacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.

In certain embodiments, a sustained release coating is applied to thesustained release spheroids, granules, or matrix multiparticulates. Insuch embodiments, the sustained-release coating may include a waterinsoluble material such as (a) a wax, either alone or in admixture witha fatty alcohol; or (b) shellac or zein. The coating is preferablyderived from an aqueous dispersion of the hydrophobic sustained releasematerial.

In certain embodiments, it is necessary to overcoat the sustainedrelease spheroids, granules, or matrix multiparticulates comprising theopioid analgesic, opioid antagonist, one or more aversive agents, andsustained release carrier with a sufficient amount of the aqueousdispersion of, e.g., alkylcellulose or acrylic polymer, to obtain aweight gain level from about 2 to about 50%, e.g., about 2 to about 25%,in order to obtain a sustained-release formulation. The overcoat may belesser or greater depending upon, e.g., the desired release rate, theinclusion of plasticizer in the aqueous dispersion and the manner ofincorporation of the same. Cellulosic materials and polymers, includingalkylcelluloses, are sustained release materials well suited for coatingthe sustained release spheroids, granules, or matrix multiparticulatesaccording to the invention. Simply by way of example, one preferredalkylcellulosic polymer is ethylcellulose, although the artisan willappreciate that other cellulose and/or alkylcellulose polymers may bereadily employed, singly or in any combination, as all or part of ahydrophobic coating according to the invention.

One commercially—available aqueous dispersion of ethylcellulose isAquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is preparedby dissolving the ethylcellulose in a water-immiscible organic solventand then emulsifying the same in water in the presence of a surfactantand a stabilizer. After homogenization to generate submicron droplets,the organic solvent is evaporated under vacuum to form a pseudolatex.The plasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, it isnecessary to intimately mix the Aquacoat® with a suitable plasticizerprior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during themanufacturing process. A hot melt of a polymer, plasticizer (dibutylsebacate), and stabilizer (oleic acid) is prepared as a homogeneousmixture, which is then diluted with an alkaline solution to obtain anaqueous dispersion which can be applied directly to the sustainedrelease spheroids, granules, or matrix multiparticulates.

In other preferred embodiments of the present invention, the sustainedrelease material comprising the sustained-release coating is apharmaceutically acceptable acrylic polymer, including but not limitedto acrylic acid and methacrylic acid copolymers, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate,poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamidecopolymer, poly(methyl methacrylate), polymethacrylate, poly(methylmethacrylate) copolymer, polyacrylamide, aminoalkyl methacrylatecopolymer, poly(methacrylic acid anhydride), and glycidyl methacrylatecopolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers. Ammonio methacrylatecopolymers are well known in the art, and are described in the NationalFormulary (NF) XVII as fully polymerized copolymers of acrylic andmethacrylic acid esters with a low content of quaternary ammoniumgroups. In order to obtain a desirable dissolution profile, it may benecessary to incorporate two or more ammonio methacrylate copolymershaving differing physical properties, such as different molar ratios ofthe quaternary ammonium groups to the neutral (meth)acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparingpH-dependent coatings which may be used in accordance with the presentinvention. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit® from Rohm GMBH andCo. Kg Darmstadt, Germany. There are several different types ofEudragit®. For example, Eudragit E is an example of a methacrylic acidcopolymer which swells and dissolves in acidic media. Eudragit L is amethacrylic acid copolymer which does not swell at about pH<5.7 and issoluble at about pH>6. Eudragit S does not swell at about pH<6.5 and issoluble at about pH>7. Eudragit RL and Eudragit RS are water swellable,and the amount of water absorbed by these polymers is pH-dependent;however, dosage forms coated with Eudragit RL and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from Rohmunder the Tradenames Eudragit® RL30D and Eudragit® RS30D, respectively.Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic andmethacrylic esters with a low content of quaternary ammonium groups, themolar ratio of ammonium groups to the remaining neutral (meth)acrylicesters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D. Themean molecular weight is about 150,000. The code designations RL (highpermeability) and RS (low permeability) refer to the permeabilityproperties of these agents. Eudragit® RURS mixtures are insoluble inwater and in digestive fluids. However, coatings formed from the sameare swellable and permeable in aqueous solutions and digestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain asustained-release formulation having a desirable dissolution profile.Desirable sustained-release formulations may be obtained, for instance,from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit®RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Ofcourse, one skilled in the art will recognize that other acrylicpolymers may also be used, such as, for example, Eudragit® L. Inembodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic sustained release material, theinclusion of an effective amount of a plasticizer in the aqueousdispersion of hydrophobic material will further improve the physicalproperties of the sustained-release coating. For example, becauseethyl-cellulose has a relatively high glass transition temperature anddoes not form flexible films under normal coating conditions, it ispreferable to incorporate a plasticizer into an ethylcellulose coatingcontaining sustained-release coating before using the same as a coatingmaterial. Generally, the amount of plasticizer included in a coatingsolution is based on the concentration of the film-former, e.g., mostoften from about 1 to about 50 percent by weight of the film-former.Concentration of the plasticizer, however, can only be properlydetermined after careful experimentation with the particular coatingsolution and method of application.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tributyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used. Methylcitrate is an especially preferred plasticizer for the aqueousdispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NT XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

In certain embodiments, the uncoated/coated sustained release spheroids,granules, or matrix multiparticulates containing the opioid analgesic;opioid antagonist; and one or more aversive agents; are cured until anendpoint is reached at which the sustained release spheroids, granules,or matrix multiparticulates provide a stable dissolution of the opioid.The curing endpoint may be determined by comparing the dissolutionprofile (curve) of the dosage form immediately after curing to thedissolution profile (curve) of the dosage form after exposure toaccelerated storage conditions of, e.g., at least one month at atemperature of 40° C. and a relative humidity of 75%. Cured formulationsare described in detail in U.S. Pat. Nos. 5,273,760; 5,286,493;5,500,227; 5,580,578; 5,639,476; 5,681,585; and 6,024,982. Otherexamples of sustained-release formulations and coatings which may beused in accordance with the present invention include those described inU.S. Pat. Nos. 5,324,351; 5,356,467; and 5,472,712.

In addition to the above ingredients, the spheroids, granules, or matrixmultiparticulates may also contain suitable quantities of othermaterials, e.g., diluents, lubricants, binders, granulating aids, andglidants that are conventional in the pharmaceutical art in amounts upto about 50% by weight of the formulation if desired. The quantities ofthese additional materials will be sufficient to provide the desiredeffect to the desired formulation.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986), incorporated by reference herein.

It has further been found that the addition of a small amount of talc tothe sustained release coating reduces the tendency of the aqueousdispersion to stick during processing, and acts as a polishing agent.

Osmotic Dosage Forms

Sustained release dosage forms according to the present invention mayalso be prepared as osmotic dosage formulations. The osmotic dosageforms preferably include a bilayer core comprising a drug layer(containing the opioid analgesic and optionally the opioid antagonistand or one or more aversive agents) and a delivery c: push layer (whichmay contain the opioid antagonist and/or one or more aversive agents),wherein the bilayer core is surrounded by a semipermeable wall andoptionally having at least one passageway disposed therein.

The expression “passageway” as used for the purpose of this invention,includes aperture, orifice, bore, pore, porous element through which theopioid analgesic (with or without the antagonist) can be pumped, diffuseor migrate through a fiber, capillary tube, porous overlay, porousinsert, microporous member, or porous composition. The passageway canalso include a compound that erodes or is leached from the wall in thefluid environment of use to produce at least one passageway.Representative compounds for forming a passageway include erodiblepoly(glycolic) acid, or poly(lactic) acid in the wall; a gelatinousfilament; a water-removable poly(vinyl alcohol); leachable compoundssuch as fluid-removable pore-forming polysaccharides, acids, salts oroxides. A passageway can be formed by leaching a compound from the wall,such as sorbitol, sucrose, lactose, maltose, or fructose, to form asustained-release dimensional pore-passageway. The passageway can haveany shape, such as round, triangular, square and elliptical, forassisting in the sustained metered release of opioid analgesic from thedosage form. The dosage form can be manufactured with one or morepassageways in spaced-apart relation on one or more surfaces of thedosage form. A passageway and equipment for forming a passageway aredisclosed in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,063,064 and4,088,864. Passageways comprising sustained-release dimensions sized,shaped and adapted as a releasing-pore formed by aqueous leaching toprovide a releasing-pore of a sustained-release rate are disclosed inU.S. Pat. Nos. 4,200,098 and 4,285,987.

In certain embodiments, the bilayer core comprises a drug layer withopioid analgesic and a displacement or push layer optionally containingthe antagonist and/or one or more aversive agents. The antagonist and/orone or more aversive agents may optionally be included in the drug layerinstead of or in addition to being included in the push layer. Incertain embodiments the drug layer may also comprise at least onepolymer hydrogel. The polymer hydrogel may have an average molecularweight of between about 500 and about 6,000,000. Examples of polymerhydrogels include but are not limited to a maltodextrin polymercomprising the formula (C₆H₁₂O₅)_(n).H₂O, wherein n is 3 to 7,500, andthe maltodextrin polymer comprises a 500 to 1,250,000 number-averagemolecular weight; a poly(alkylene oxide) represented by, e.g., apoly(ethylene oxide) and a poly(propylene oxide) having a 50,000 to750,000 weight-average molecular weight, and more specificallyrepresented by a poly(ethylene oxide) of at least one of 100,000,200,000, 300,000 or 400,000 weight-average molecular weights; an alkalicarboxyalkylcellulose, wherein the alkali is sodium or potassium, thealkyl is methyl, ethyl, propyl, or butyl of 10,000 to 175,000weight-average molecular weight; and a copolymer of ethylene-acrylicacid, including methacrylic and ethacrylic acid of 10,000 to 500,000number-average molecular weight.

In certain embodiments of the present invention, the delivery or pushlayer comprises an osmopolymer. Examples of an osmopolymer include butare not limited to a member selected from the group consisting of apolyalkylene oxide and a carboxyalkylcellulose. The polyalkylene oxidepossesses a 1,000,000 to 10,000,000 weight-average molecular weight. Thepolyalkylene oxide may be a member selected from the group consisting ofpolymethylene oxide, polyethylene oxide, polypropylene oxide,polyethylene oxide having a 1,000,000 average molecular weight,polyethylene oxide comprising a 5,000,000 average molecular weight,polyethylene oxide comprising a 7,000,000 average molecular weight,cross-linked polymethylene oxide possessing a 1,000,000 averagemolecular weight, and polypropylene oxide of 1,200,000 average molecularweight. Typical osmopolymer carboxyalkylcellulose comprises a memberselected from the group consisting of alkali carboxyalkylcellulose,sodium carboxymethylcellulose, potassium carboxymethylcellulose, sodiumcarboxyethylcellulose, lithium carboxymethylcellulose, sodiumcarboxyethylcellulose, carboxyalkylhydroxyalkylcellulose,carboxymethylhydroxyethyl cellulose, carboxyethylhydroxyethylcelluloseand carboxymethylhydroxypropylcellulose. The osmopolymers used for thedisplacement layer exhibit an osmotic pressure gradient across thesemipermeable wall. The osmopolymers imbibe fluid into dosage form,thereby swelling and expanding as an osmotic hydrogel (also known asosmogel), whereby they push the contents of the drug layer from theosmotic dosage form.

The push layer may also include one or more osmotically effectivecompounds also known as osmagents and as osmotically effective solutes.They imbibe an environmental fluid, for example, from thegastrointestinal tract, into dosage form and contribute to the deliverykinetics of the displacement layer. Examples of osmotically activecompounds comprise a member selected from the group consisting ofosmotic salts and osmotic carbohydrates. Examples of specific osmagentsinclude but are not limited to sodium chloride, potassium chloride,magnesium sulfate, lithium phosphate, lithium chloride, sodiumphosphate, potassium sulfate, sodium sulfate, potassium phosphate,glucose, fructose and maltose.

The push layer may optionally include a hydroxypropylalkylcellulosepossessing a 9,000 to 450,000 number-average molecular weight. Thehydroxypropylalkylcellulose is represented by a member selected from thegroup consisting of hydroxypropylmethylcellulose,hydroxypropylethylcellulose, hydroxy propyl isopropyl cellulose,hydroxypropylbutylcellulose, and hydroxypropylpentylcellulose.

The push layer may also optionally comprise an antioxidant to inhibitthe oxidation of ingredients. Some examples of antioxidants include butare not limited to a member selected from the group consisting ofascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixtureof 2 and 3 tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene,sodium isoascorbate, dihydroguaretic acid, potassium sorbate, sodiumbisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate,vitamin E, 4-chloro-2,6-ditertiary butylphenol, alphatocopherol, andpropylgallate.

In certain alternative embodiments, the dosage form comprises asubstantially homogenous core comprising opioid analgesic, an opioidantagonist, one or more aversive agents, a pharmaceutically acceptablepolymer (e.g., polyethylene oxide), optionally a disintegrant (e.g.,polyvinylpyrrolidone), optionally an absorption enhancer (e.g., a fattyacid, a surfactant, a chelating agent, a bile salt, etc.). Thesubstantially homogenous core is surrounded by a semipermeable wallhaving a passageway (as defined above) for the release of the opioidanalgesic, the opioid antagonist, and the one or more aversive agents.

In certain embodiments, the semipermeable wall comprises a memberselected from the group consisting of a cellulose ester polymer, acellulose ether polymer and a cellulose ester-ether polymer.Representative wall polymers comprise a member selected from the groupconsisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di- and tricellulose alkenylates, and mono-, di- andtricellulose alkinylates. The poly(cellulose) used for the presentinvention comprises a number-average molecular weight of 20,000 to7,500,000.

Additional semipermeable polymers for the purpose of this inventioncomprise acetaldehyde dimethycellulose acetate, cellulose acetateethylcarbamate, cellulose acetate methylcarbamate, cellulose diacetate,propylcarbamate, cellulose acetate diethylaminoacetate; semipermeablepolyamide; semipermeable polyurethane; semipermeable sulfonatedpolystyrene; semipermeable cross-linked polymer formed by thecoprecipitation of a polyanion and a polycation as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,876;semipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Pat.No. 3,133,132; semipermeable crosslinked polystyrenes; semipermeablecross-linked poly(sodium styrene sulfonate); semipermeable crosslinkedpoly(vinylbenzyltrimethyl ammonium chloride); and semipermeable polymerspossessing a fluid permeability of 2.5×10⁻⁸ to 2.5×10² (cm²/hr·atm)expressed per atmosphere of hydrostatic or osmotic pressure differenceacross the semipermeable wall. Other polymers useful in the presentinvention are known in the art in U.S. Pat. Nos. 3,845,770; 3,916,899and 4,160,020; and in Handbook of Common Polymers, Scott, J. R. and W.J. Roff, 1971, CRC Press, Cleveland, Ohio.

In certain embodiments, preferably the semipermeable wall is nontoxic,inert, and it, maintains its physical and chemical integrity during thedispensing life of the drug. In certain embodiments, the dosage formcomprises a binder. An example of a binder includes, but is not limitedto a therapeutically acceptable vinyl polymer having a 5,000 to 350,000viscosity-average molecular weight, represented by a member selectedfrom the group consisting of poly-n-vinyiamide, poly-n-vinylacetamide,poly(vinyi pyrrolidone), also known as poly-n-vinylpyrrolidone,poly-n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, andpoly-n-vinyl-pyrrolidone copolymers with a member selected from thegroup consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinylfluoride, vinyl butyrate, vinyl laureate, and vinyl stearate. Otherbinders include for example, acacia, starch, gelatin, andhydroxypropylalkylcellulose of 9,200 to 250,000 average molecularweight.

In certain embodiments, the dosage form comprises a lubricant, which maybe used during the manufacture of the dosage form to prevent sticking todie wall or punch faces. Examples of lubricants include but are notlimited to magnesium stearate, sodium stearate, stearic acid, calciumstearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid,sodium stearyl fumarate, and magnesium palmitate.

Transdermal Delivery Systems

The formulations of the present invention may be formulated as atransdermal delivery system, such as transdermal patches. In certainembodiments of the present invention, a transdermal patch comprises anopioid agonist contained in a reservoir or a matrix, and an adhesivewhich allows the transdermal device to adhere to the skin, allowing thepassage of the active agent from the transdermal device through the skinof the patient, with the inclusion of the aversive agents and opioidantagonists as disclosed herein which are not releasable when the dosageform is administered intact but which are releasable when the dosageform is broken or tampered with in order to release the opioid from thetransdermal system.

Transdermal delivery system providing a controlled-release of an opioidagonist is known. For example, Duragesic® patch (commercially availablefrom Janssen Pharmaceutical) contains an opioid agonist (fentanyl) andis said to provide adequate analgesia for up to 48 to 72 hours (2 to 3days). This formulation can be reformulated with an aversive agent andantagonist as disclosed herein.

There are several types of transdermal formulations of buprenorphinereported in the literature. See, for example, U.S. Pat. No. 5,240,711(Hille et al.), U.S. Pat. No. 5,225,199 (Hidaka et al.), U.S. Pat. No.5,069,909 (Sharma et al.), U.S. Pat. No. 4,806,341 (Chien et al.), andU.S. Pat. No. 5,026,556 (Drust et al.), all of which are herebyincorporated by reference. These transdermal devices can also bereformulated with the aversive agents and antagonists as disclosedherein.

The transdermal delivery system used in the present invention may alsobe prepared in accordance with U.S. Pat. No. 5,069,909 (Sharma et al.),hereby incorporated by reference. This patent describes a laminatedcomposite for administering buprenorphine transdermally to treat pain.The transdermal delivery system used in the present invention may alsobe prepared in accordance with U.S. Pat. No. 4,806,341 (Chien et al.),hereby incorporated by reference. This patent describes a transdermalmorphinan narcotic analgesic or antagonist (including buprenorphine)pharmaceutical polymer matrix dosage unit having a backing layer whichis substantially impervious to the buprenorphine, and a polymer matrixdisc layer which is adhered to the backing layer and which hasmicrodispersed therein effective dosage amounts of the buprenorphine.

The transdermal delivery system used in the present invention may alsobe that described in U.S. Pat. No. 5,026,556 (Drust et al.), herebyincorporated by reference. Therein, compositions for the transdermaldelivery of buprenorphine comprise buprenorphine in a carrier of a polarsolvent material selected from the group consisting of C₃-C₄ diols,C₃-C₆ triols, and mixtures thereof, and a polar lipid material selectedfrom the group consisting of fatty alcohol esters, fatty acid esters,and mixtures thereof; wherein the polar solvent material and the lipidmaterial are present in a weight ratio of solvent material:lipidmaterial of from 60:40 to about 99:1. The transdermal delivery systemused in the present invention may also be that described in U.S. Pat.No. 4,588,580 (Gale, et. al.), hereby incorporated by reference. Thatsystem comprises a reservoir for the drug having a skin proximal,material releasing surface area in the range of about 5-100 cm² andcontaining between 0.1 and 50% by weight of a skin permeable form of thebuprenorphine. The reservoir contains an aqueous gel comprising up toabout 47-95% ethanol, 1-10% gelling agent, 0.1-10% buprenorphine, andrelease rate controlling means disposed in the flow path of the drug tothe skin which limits the flux of the buprenorphine from the systemthrough the skin.

The transdermal delivery system used in the present invention may alsobe that described in PCT/US01/04347 to Oshlack et al.

The present invention is contemplated to encompass all transdermalformulations, e.g., the technologies described above, with the inclusionof an aversive agent and antagonist, such that the dosage form detersabuse of the opioid therein.

The aversive agent and antagonist in non-releasable form whenadministered intact can be formulated in accordance with U.S. Pat. No.5,149,538 to Granger, hereby incorporated by reference. Alternatively,the aversive agent and the opioid agonist can be separated from theopioid by a layer which becomes disrupted when the dosage form istampered with, thereby mixing the aversive agent with the opioidagonist. Alternatively, a combination of both systems can be used.

Suppositories

The controlled release formulations of the present invention may beformulated as a pharmaceutical suppository for rectal administrationcomprising an opioid analgesic, opioid antagonist, and at least oneaversive agent in a controlled release matrix, and a suppository vehicle(base). Preparation of controlled release suppository formulations isdescribed in, e.g., U.S. Pat. No. 5,215,758.

The suppository base chosen should be compatible with the agent(s) ofthe present invention. Further, the suppository base is preferablynon-toxic and nonirritating to mucous membranes, melts or dissolves inrectal fluids, and is stable during storage.

In certain preferred embodiments of the present invention for bothwater-soluble and water-insoluble drugs, the suppository base comprisesa fatty acid wax selected from the group consisting of mono-, di- andtriglycerides of saturated, natural fatty acids of the chain length C₁₂to C₁₈.

In preparing the suppositories of the present invention other excipientsmay be used. For example, a wax may be used to form the proper shape foradministration via the rectal route. This system can also be usedwithout wax, but with the addition of diluent filled in a gelatincapsule for both rectal and oral administration.

Examples of suitable, commercially available mono-, di- andtriglycerides include saturated natural fatty acids of the 12-18 carbonatom chain sold under the trade name Novata™ (types AB, AB, B, BC, BD,BBC, E, BCF, C, D and 299), manufactured by Henkel, and Witepsol™ (typesH5, H12, H15, H175, H185, H19, H32, H35, H39, H42, W25, W31, W35, W45,S55, S58, E75, E76 and E85), manufactured by Dynamit Nobel.

Other pharmaceutically acceptable suppository bases may be substitutedin whole or in part for the above-mentioned mono-, di- andtriglycerides. The amount of base in the suppository is determined bythe size (i.e. actual weight) of the dosage form, the amount of base(e.g., alginate) and drug used. Generally, the amount of suppositorybase is from about 20 percent to about 90 percent by weight of the totalweight of the suppository. Preferably, the amount of base in thesuppository is from about 65 percent to about 80 percent, by weight ofthe total weight of the suppository.

In certain embodiments of the dosage forms of the present invention mayalso include a surfactant. Surfactants useful in accordance with thepresent invention, include for example, ionic and nonionic surfactantsor wetting agents commonly used in the formulation of pharmaceuticals,including but not limited to castor oil derivatives, cholesterol,polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fattyacid esters, poloxamers, polysorbates, polyoxyethylene sorbitan fattyacid esters, polyoxyethylene compounds, monoglycerides or ethoxylatedderivatives thereof, diglycerides or polyoxyethylene derivativesthereof, sodium docusate, sodium laurylsulfate, cholic acid orderivatives thereof, ethoxylated alcohols, ethoxylated esters,ethoxylated amides, polyoxypropylene compounds, propoxylated alcohols,ethoxylated/propoxylated block polymers, propoxylated esters,alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols,ethylene glycol esters, diethylene glycol esters, propylene glycolesters, glycerol esters, polyglycerol fatty acid esters, SPAN's (e.g.,sorbitan esters), TWEEN's (i.e., sucrose esters), glucose (dextrose)esters, alkali metal sulfates, quaternary ammonium compounds,amidoamines, and aminimides, simethicone, lecithins, alcohols,phospholipids, and mixtures thereof.

Mixed surfactant/wetting agents useful in accordance with the presentinvention include, for example, sodium lauryl sulfate/polyethyleneglycol (PEG) 6000 and sodium lauryl sulfate/PEG 6000/stearic acid, etc.

In certain embodiments of the present invention, the dosage form mayalso include an emulsifying agent. Emulsifying agents useful inaccordance with the present invention include, for example,monoglycerides, sucrose/fatty acid esters, polyglycerol/fatty acidesters, sorbitan/fatty acid esters, lecithins, potassium and sodiumsalts of rosin acids and higher fatty acids, as well as sulfates andsulfonates of these acids, amine salts of hydroxylamines of long-chainfatty acid esters, quaternary ammonium salts such asstearyl-dimethylbenzylammonium chloride andtridecylbenzenehydroxyethylimidazole chloride, phosphoric esters ofhigher alcohols such as capryl and octyl alcohol, and monoesters ofoleic acid and pentaerythritol such as sorbitan monooleates, andmixtures thereof.

The oral dosage form and methods for use of the present invention mayfurther include, in addition to an opioid analgesic and opioidantagonist, one or more drugs that may or may not act synergisticallywith the opioid analgesic. Thus, in certain embodiments, a combinationof two opioid analgesics may be included in the dosage form. Forexample, the dosage form may include two opioid analgesics havingdifferent properties, such as half-life, solubility, potency, and acombination of any of the foregoing.

In yet further embodiments; one or more opioid analgesic is included anda further non-opioid drug is also included. Such non-opioid drugs wouldpreferably provide additional analgesia, and include, for example,aspirin, acetaminophen; non-steroidal anti-inflammatory drugs(“NSAIDS”), e.g., ibuprofen, ketoprofen, etc.; N-methyl-D-aspartate(NMDA) receptor antagonists, e.g., a morphinan such as dextromethorphanor dextrorphan, or ketamine; cyclooxygenase-II inhibitors (“COX-IIinhibitors”); and/or glycine receptor antagonists.

In certain preferred embodiments of the present invention, the inventionallows for the use of lower doses of the opioid analgesic by virtue ofthe inclusion of an additional non-opioid analgesic, such as an NSAID ora COX-2 inhibitor. By using lower amounts of either or both drugs, theside effects associated with effective pain management in humans arereduced.

Suitable non-steroidal anti-inflammatory agents, including ibuprofen,diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen,ketoprofen, indoprofen, piro-profen, carprofen, oxaprozin, pramoprofen,muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac,mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid,tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam orisoxicam, and the like. Useful dosages of these drugs are well known tothose skilled in the art.

N-methyl-D-aspartate (NMDA) receptor antagonists are well known in theart, and encompass, for example, morphinans such as dextromethorphan ordextrorphan, ketamine, or pharmaceutically acceptable salts thereof. Forpurposes of the present invention, the term “NMDA antagonist” is alsodeemed to encompass drugs that block a major intracellular consequenceof NMDA-receptor activation, e.g. a ganglioside such as GM₁ or GT_(1b) aphenothiazine such as trifluoperazine or a naphthalenesulfonamide suchas N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide. These drugs arestated to inhibit the development of tolerance to and/or dependence onaddictive drugs, e.g., narcotic analgesics such as morphine, codeine,etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838 (both to Mayer, et al.),and to treat chronic pain in U.S. Pat. No. 5,502,058 (Mayer, et al.),all of which are hereby incorporated by reference. The NMDA antagonistmay be included alone, or in combination with a local anesthetic such aslidocaine, as described in these Mayer, et. al. patents.

The treatment of chronic pain via the use of glycine receptorantagonists and the identification of such drugs is described in U.S.Pat. No. 5,514,680 (Weber, et al.).

COX-2 inhibitors have been reported in the art and many chemicalstructures are known to produce inhibition of cyclooxygenase-2. COX-2inhibitors are described, for example, in U.S. Pat. Nos. 5,616,601;5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,474,995;5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and5,130,311, all of which are hereby incorporated by reference. Certainpreferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697,flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid(6-MNA), MK-966 (also known as Vioxx), nabumetone (prodrug for 6-MNA),nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinations thereof.Dosage levels of COX-2 inhibitor on the order of from about 0.005 mg toabout 140 mg per kilogram of body weight per day are therapeuticallyeffective in combination with an opioid analgesic. Alternatively, about0.25 mg to about 7 g per patient per day of a COX-2 inhibitor isadministered in combination with an opioid analgesic.

In yet further embodiments, a non-opioid drug can be included whichprovides a desired effect other than analgesia, e.g., antitussive,expectorant, decongestant, antihistamine drugs, local anesthetics, andthe like.

The invention disclosed herein is meant to encompass the use pf anypharmaceutically acceptable salts thereof of the disclosed opioidanalgesics. The pharmaceutically acceptable salts include, but are notlimited to, metal salts such as sodium salt, potassium salt, secium saltand the like; alkaline earth metals such as calcium salt, magnesium saltand the like; organic amine salts such as triethylamine salt, pyridinesalt, picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like;inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts such as arginate, asparginate, glutamate and the like.

Some of the opioid analgesics disclosed herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The present invention is also meant toencompass the use of any of such possible forms as well as their racemicand resolved forms and mixtures thereof. When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended to includeboth E and Z geometric isomers. The use of all tautomers are intended tobe encompassed by the present invention as well.

The oral dosage forms of the present invention may be in the form oftablets, troches, lozenges, powders or granules, hard or soft capsules,microparticles (e.g., microcapsules, microspheres and the like), buccaltablets, etc.

In certain embodiments, the present invention provides for a method ofpreventing abuse of an oral controlled release dosage form of an opioidanalgesic comprising preparing the dosage forms as described above.

In certain embodiments, the present invention provides for a method ofpreventing diversion of an oral controlled release dosage form of anopioid analgesic comprising preparing the dosage forms as describedabove.

In certain embodiments, the present invention provides for a method oftreating pain by administering to a human patient the dosage formsdescribed above.

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

Example 1 A 20 mg Oxycodone Formulation was Prepared Containing Naloxoneas the Antagonist and Xanthan Gum as the Aversive Agent

In this example, a small amount of xanthan gum is added to the oxycodoneformulation during the granulation process. Other gelling agents such ascurdlan, carrageenan, alginates, pectin, gelatin, furcelleran, agar,guar locust bean gum, tara gum, tragacanth, acacia, glucomannans,karaya, starch and starch derivatives, egg white powder, lacto albumin,soy protein, Jargel, gellan gum, welan gum, rhamsan gum, and the like,could also be used as gelling agents. Other semi-synthetic materialssuch as chitosan, pullulan, polylaevulan, hydroxypropyl cellulose,methylcellulose, hydroxypropylmethyl cellulose, carboxymethyl celluloseethylhydroxyethyl cellulose, all ether derivatives of cellulose, and thelike, could also be used as alternate gelling materials.

TABLE 1 Ingredients Amt/Unit (mg) Amount/Batch (gm) Oxycodone HCl 20.0209.6* Spray Dried Lactose 59.25 592.5 Povidone 5.0 50.0 Eudragit RS30D(solids) 10.0 100 Triacetin 2.0 20.0 Naloxone HCl 0.61 6.12** Xanthangum 9.0 90.0 Stearyl Alcohol 25.0 250.0 Talc 2.5 25.0 Magnesium Stearate1.25 12.5 Opadry Pink Y-S-14518A 5.0 50.0 *adjusted for 99.6% assay and4.2% residual moisture. **adjusted for 99.23% assay and 0.5% residualmoisture.

Process

-   1. Dispersion: Dissolve naloxone HCl in water and the solution is    added to the Eudragit/Triacetin dispersion.-   2. Granulation: Spray the Eudragit/Triacetin dispersion onto the    oxycodone HCl, Spray Dried Lactose, xanthan gum and Povidone using a    fluid bed granulator.-   3. Milling: Discharge the granulation and pass through a mill.-   4. Waxing: Melt the stearyl alcohol and add to the milled    granulation using a mixer. Allow to cool.-   5. Milling: Pass the cooled granulation through a mill.-   6. Lubrication: Lubricate the granulation with talc and magnesium    stearate using a mixer.-   7. Compression: Compress the granulation into tablets using a tablet    press.

Example 2 A 40 mg Oxycodone Formulation was Prepared Containing Naloxoneas the Antagonist and Xanthan Gum as the Aversive Agent

To determine the effect of varying amount of xanthan gum on the gellingproperty and dissolution rate of an oxycodone tablet, three levels ofxanthan gum were added to 40 mg oxycodone granulation and compressedinto tablets. Oxycodone recovery from water extraction of the tablet andthe drug release rate were determined. The oxycodone granulationformulation of Example 2 is listed in Table 2 below.

TABLE 2 Ingredients Amt/Unit (mg) Oxycodone HCl 40.0 Spray Dried Lactose39.25 Povidone 5.0 Eudragit RS30D (solids) 10.0 Triacetin 2.0 NaloxoneHCL 0.9 Stearyl Alcohol 25.0 Talc 2.5 Magnesium Stearate 1.25 Total125.9

Example 2A to 2C are prepared adding different amounts (3 mg, 5 mg, and9 mg) of xanthan gum to a 125.9 mg oxycodone granulation of Example 2.

Example 2A

Ingredients Amt/Unit (mg) Oxycodone granulation 125.9 Xanthan gum 3Total 128.9

Example 2B

Ingredients Amt/Unit (mg) Oxycodone granulation 125.9 Xanthan gum 5Total 130.9

Example 2C

Ingredients Amt/Unit (mg) Oxycodone granulation 125.9 Xanthan gum 9Total 134.9

Process

-   1. Dispersion: Dissolve naloxone HCl in water and the solution is    added to the Eudragit/Triacetin dispersion.-   2. Granulation: Spray the Eudragit/Triacetin dispersion onto the    Oxycodone HCl, Spray Dried Lactose and Povidone using a fluid bed    granulator.-   3. Milling: Discharge the granulation and pass through a mill.-   4. Waxing: Melt the stearyl alcohol and add to the milled    granulation using a mixer. Allow to cool.-   5. Milling: Pass the cooled granulation through a mill.-   6. Lubrication: Lubricate the granulation with talc and magnesium    stearate using a mixer.-   7. Add xanthan gum (3 levels) to the granulation and mix well.-   8. Compression: Compress the granulation into tablets using a tablet    press.

Example 3

The granulation of Example 2 was compressed into tablets using a tabletpress without the addition of xanthan gum, and Examples 2, 2A-C weretested under the following dissolution conditions and gave the resultslisted in Table 3 below.

-   1. Apparatus: USP Type II (paddle), 150 rpm.-   2. Medium: 700 ml SGF for first hour, thereafter made 900 ml with    phosphate buffer to pH 7.5.-   3. Sampling time: 1, 2, 4, 8, 12, 18 and 24 hours.-   4. Analytical: High Performance Liquid Chromatography.

TABLE 3 Dissolution Results % Dissolved Ex. 2 Ex. 2A Ex. 2B Ex. 2C (no(3 mg (5 mg (9 mg xanthan Time (hrs) xanthan) xanthan) xanthan) added)Spec 1 48 43 46 45 28-58 4 86 73 79 75 55-88 12 101 98 99 93 >80

The dissolution results show that all the tablets prepared have similardissolution profiles. The inclusion of xanthan gum does not appear tosubstantially change the oxycodone dissolution rate.

When 1 mL of water was added to the tablets containing xanthan gum on atea spoon, the solution was not viscous. However, when the samples wereheated and allowed to cool, the samples became very viscous. It was verydifficult to withdraw this gel-like solution into a syringe forinjection.

Example 4 A 20 mg Oxycodone Formulation Containing Naloxone as theAntagonist and a Bittering Agent as the Aversive Agent was Prepared

In this example, a small amount of denatonium benzoate is added to anoxycodone formulation during the granulation process. The bitter tastewould reduce the abuse of oxycodone by oral or intranasal route. Theoxycodone formulation of Example 4 is listed in Table 4 below.

TABLE 4 Ingredients Amt/Unit (mg) Amount/Batch (gm) Oxycodone HCl 20.0209.6* Spray Dried Lactose 59.25 592.5 Povidone 5.0 50.0 Eudragit RS30D(solids) 10.0 100 Triacetin 2.0 20.0 Naloxone HCl 0.61 6.12** Denatoniumbenzoate 0.07 0.68 Stearyl Alcohol 25.0 250.0 Talc 2.5 25.0 MagnesiumStearate 1.25 12.5 Opadry Pink Y-S-14518A 5.0 50.0 *adjusted for 99.6%assay and 4.2% residual moisture. **adjusted for 99.23% assay and 0.5%residual moisture.

Process

-   1. Dispersion: Dissolve naloxone HCL and denatonium benzoate in    water and the solution is added to the Eudragit/Triacetin    dispersion.-   2. Granulation: Spray the Eudragit/Triacetin dispersion onto the    Oxycodone HCl, Spray Dried Lactose and Povidone using a fluid bed    granulator.-   3. Milling: Discharge the granulation and pass through a mill.-   4. Waxing: Melt the stearyl alcohol and add to the milled    granulation using a mixer. Allow to cool.-   5. Milling: Pass the cooled granulation through a mill.-   6. Lubrication: Lubricate the granulation with talc and magnesium    stearate using a mixer.-   7. Compression: Compress the granulation into tablets using a tablet    press.

Example 5

In Example 5, a substantially non-releasable form of a bittering agent(denatonium benzoate) is prepared by coating denatonium benzoateparticles with a coating that renders the denatonium benzoatesubstantially non-releasable. The formulation of Example 5 is listed inTable 5 below.

TABLE 5 Amt/unit Ingredients (mg) LOADING denatonium benzoate 0.07 SugarSpheres (30/35 mesh) 50.0 Opadry White Y-5-7068 2.5 Purified Water 42.5*OVERCOATING Opadry White Y-5-7068 3.02 Purified Water 17.11* NON-RELEASECOATING (FOR RENDERING BITTERING AGENT SUBSTANTIALLY NON- RELEASABLE)Eudragit RS30D (dry wt.) 12.10 Triethyl Citrate 2.42 Talc 4.84 PurifiedWater 49.21* OVERCOATING Opadry White Y-5-7068 4.12 Purified Water23.35* Total 79.07 *Remains in product as residual moisture only.

Process:

-   1. Solution Preparation Dissolve the denatonium benzoate in Purified    Water. Once dissolved, add the Opadry White and continue mixing    until a homogeneous dispersion is yielded.-   2. Loading Apply the above dispersion onto the Sugar Spheres using a    fluid bed coating machine.-   3. Overcoating Prepare an overcoating solution by dispersing Opadry    White in Purified Water. Apply this dispersion over the sugar    spheres loaded with denatonium benzoate using a fluid bed coating    machine.-   4. Retardant Coating Prepare the non-release coating solution by    mixing the Eudragit RS30D, Triethyl Citrate, Talc, and Purified    Water. Apply this dispersion over the loaded and overcoated sugar    spheres using a fluid bed coating machine.-   5. Overcoating Prepare a second overcoating solution by dispersing    Opadry White in Purified Water. Apply this dispersion over the    non-release coated denatonium benzoate spheres using a fluid bed    coating machine-   6. Curing Cure the spheres at 45° C. for approximately 48 hours.

Example 6

In Example 6, a substantially non-releasable form of a bittering agent(denatonium benzoate) is prepared as denatonium benzoate containinggranulates. The granulates are comprised of denatonium benzoatedispersed in a matrix that renders the denatonium benzoate substantiallynon-releasable. The formulation of Example 6 is listed in Table 6 below.

TABLE 6 Amt/unit Ingredient (mg) Denatonium benzoate 0.07 DicalciumPhosphate 53.0 Poly (DI-Lactide-Co- 12.0 Glycolide) polymer (PLGA)MW~100,000 Ethyl Acetate Total 65.07 *Used as a vehicle for applicationof PLGA polymer.

Process:

-   -   1. Solution Preparation Dissolve PLGA in Ethyl Acetate by        mixing.    -   2. Granulation Place the denatonium benzoate, and Dicalcium        Phosphate in a fluid bed coating machine and granulate by        spraying the above solution.

Example 7

In Example 7, a substantially non-releasable form of a bittering agent(denatonium benzoate) is prepared as denatonium benzoate extrudedpellets. The formulation of Example 7 is listed in Table 7 below.

TABLE 7 Amt/unit Ingredient (mg) Denatonium benzoate 0.07 Eudragit RSPO180.0 Stearyl Alcohol 55.0 Total 235.07

Process:

-   1. Milling Pass stearyl alcohol flakes through an impact mill.-   2. Blending Mix Denatonium benzoate, Eudragit, and milled Stearyl    Alcohol in a twin shell blender.-   3. Extrusion Continuously feed the blended material into a twin    screw extruder and collect the resultant strands on a conveyor.-   4. Cooling Allow the strands to cool on the conveyor.-   5. Pelletizing Cut the cooled strands into pellets using a    Pelletizer.-   6. Screening Screen the pellets and collect desired sieve portion.

Example 8 Naltrexone HCl Beads

In Example 8, Naltrexone HCl beads for incorporation into capsules wereprepared having the following formulation in Table 8 below.

TABLE 8 Amt/unit Ingredients (mg) Step 1. Drug layering Naltrexone HCl2.1 Non-pareil beads (30/35 mesh) 39.98 Opadry Clear 0.4(Hydroxypropymethyl cellulose) Sodium ascorbate 0.027 Ascorbic acid 0.05Step 2. Anionic polymer Eudragit L30D (dry) 2.164 coat Triethyl Citrate0.433 Cabosil 0.108 Step 3. Sustained release Eudragit RS30D (dry)17.475 coat Triethyl citrate 3.495 Cabosil 0.874 Step 4. Seal coatOpadry Clear 1.899 (Hydroxypropylmethyl cellulose) Cabosil 0.271 Total(on dry basis) 69.287

Process:

-   1. Dissolve naltrexone HCl, ascorbic acid, sodium ascorbate and    Opadry Clear in water. Spray the drug solution onto non-pareil beads    in a fluid bed coater with Wurster insert.-   2. Disperse Eudragit L30D, Triethyl citrate, and Cabosil in water.    Spray the dispersion onto the drug-loaded beads in the fluid bed    coater.-   3. Disperse Eudragit RS30D, triethyl citrate, and Cabosil in water.    Spray the dispersion onto the beads in the fluid bed coater.-   4. Dissolve Opadry Clear in water. Spray the solution onto the beads    in the fluid bed coater.-   5. Cure the beads at 60° C. for 24 hours.

Example 9 Naltrexone Multiparticulates

A naltrexone melt extruded multiparticulate formulation was prepared.The melt extruded multiparticulate formulation is listed in Table 9below.

TABLE 9 Ingredients Amt/Unit (mg) Naltrexone HCl 2.0 Eudragit RSPO 88.0Stearyl alcohol 15.0 Stearic acid 15.0 BHT 1.0 Total 121.0

Process:

-   1. Blend milled Stearic acid, stearyl alcohol, Naltrexone HCl, BHT,    and Eudragit RSPO using a V-blender.-   2. Extrude the mixture using a Powder Feeder, Melt Extruder    (equipped with the 6×1 mm die head), Conveyor, Lasermike, and    Pelletizer.    -   Powder feed rate-4.2 kg/hr; vacuum-˜980 mBar    -   Conveyor-such that diameter of extrudate is 1 mm    -   Pelletizer-such that pellets are cut to 1 mm in length-   3. Screen pellets using #16 mesh and #20 mesh screens. Collect    material that passes through the #16 mesh screen and is retained on    the #20 mesh screen.-   4. Fill size #2 clear gelatin capsules with the pellets. Range: NLT    114 mg and NMT 126 mg.

Example 10 Naltrexone CR Beads

A naltrexone sustained release bead formulation was prepared which canbe incorporated into an opioid controlled release granulation andcompressed into tablets. The naltrexone controlled release beadformulation is listed in Table 10 below.

TABLE 10 Amt/unit* Ingredients (mg) Step 1. Drug layering Naltrexone HCl0.609 Non-pareil beads (30/35 mesh) 67.264 Opadry Clear 0.547 Step 2.Seal coat Eudragit L 2.545 Triethyl citrate 0.636 Glyceryl monostearate0.239 Step 3. Sustained release Eudragit RS30D (dry) 43.789 coatTriethyl citrate 8.758 Cabosil 2.189 Step 4. Seal coat Opadry Clear2.053 (Hydroxypropylmethyl cellulose) Cabosil 1.368 Total 130

Process:

-   1. Dissolve naltrexone HCl and Opadry (HPMC) in water. Spray the    drug solution onto non-pareil beads in a fluid bed coater with    Wurster insert.-   2. Disperse Eudragit L, Triethyl citrate, and glyceryl monostearate    in water. Spray the dispersion onto the drug-loaded beads in the    fluid bed coater.-   3. Disperse Eudragit RS, triethyl citrate, and Cabosil in water.    Spray the dispersion onto the beads in the fluid bed coater.-   4. Dissolve Opadry in water. Spray the solution onto the beads in    the fluid bed coater.-   5. Cure the beads at 60° C. for 24 hours.

Example 11 Controlled Release Oxycodone

In Example 11, a sustained release 20 mg controlled release oxycodoneformulation was prepared having the formulation listed in Table 11below.

TABLE 11 Ingredients Amt/Unit (mg) Oxycodone HCl 20.0 Spray DriedLactose 59.25 Povidone 5.0 Eudragit RS30D (solids) 10.0 Triacetin 2.0Stearyl Alcohol 25.0 Talc 2.5 Magnesium Stearate 1.25 Opadry PinkY-S-14518A 4.0 Total 129.0

Process:

-   1. Granulation: Spray the Eudragit/Triacetin dispersion onto the    Oxycodone HCl, Spray Dried Lactose and Povidone using a fluid bed    granulator.-   2. Milling: Discharge the granulation and pass through a mill.-   3. Waxing: Melt the stearyl alcohol and add to the milled    granulation using a mixer. Allow to cool.-   4. Milling: Pass the cooled granulation through a mill.-   5. Lubrication: Lubricate the granulation with talc and magnesium    stearate using a mixer.-   6. Compression: Compress the granulation into tablets using a tablet    press.-   7. Film coating: Apply an aqueous film coat to the tablets.

Example 12

In Example 12, naltrexone beads prepared in accordance with Example 16are incorporated into the sustained release 20 mg oxycodone tabletsprepared in accordance with Example 11 and having the formula listed inTable 12 below.

TABLE 12 Amt/unit* Ingredients (mg) Step 1. Granulation Oxycodone HCl20.0 Spray Dried Lactose 59.25 Povidone 5.0 Eudragit RS30D (dry) 10.0Triacetin 2.0 Stearyl alcohol 25.0 Talc 2.5 Magnesium 1.25 Step 2.Combination OxyContin granulation (Example 125 tablet 3) Naltrexone CRbeads (Formula 2) 140

Process:

-   1. Spray the Eudragit/triacetin dispersion onto the Oxycodone HCl,    spray dried lactose and povidone using a fluid bed granulator.-   2. Discharge the granulation and pass through a mill.-   3. Melt the stearyl alcohol and add to the milled granulation using    a mill. Allow to cool.-   4. Pass the cooled granulation through a mill.-   5. Lubricate the granulation with talc and magnesium stearate. Using    a mixer.-   6. Mix naltrexone beads with the above granulation and compress into    tablets.

Alternate Process:

-   -   1. Spray the Eudragit/triacetin dispersion onto the Oxycodone        HCl, spray dried lactose and povidone using a fluid bed        granulator.    -   2. Discharge the granulation and pass through a mill.    -   3. Mix naltrexone beads (example 2) with the above granulation        in a Hobar mixer.    -   4. Melt the stearyl alcohol and add to the above mixture. Allow        to cool.    -   5. Pass the cooled granulation through a mill.    -   6. Lubricate the granulation with talc and magnesium stearate        using a mixer.    -   7. Compress into tablets.

Releasable naltrexone can be a) overcoated onto the pellets by e.g.,including it in an Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an amount to have a desiredpharmacological effect as disclosed herein and can be immediate orsustained release.

One or more aversive agents as described herein can be incorporated intothe oxycodone tablets by one skilled in the art. The one or moreaversive agents may be in releasable, non-releasable, or substantiallynon-releasable form or a combination thereof.

Example 13 Controlled Release Hydrocodone

A sustained release hydrocodone formulation was prepared having theformula in Table 13 below.

TABLE 13 Ingredients Amt/Unit (mg) Amt/Batch (g) Hydrocodone Bitartrate15.0 320.0 Eudragit RSPO 76.0 1520.0 Eudragit RLPO 4.0 80.0 StearylAlcohol 25.0 500.0 Total 120.0 2400.0

Process:

-   1. Blend milled Stearyl Alcohol, Eudragit RLPO, Hydrocodone    Bitartrate, and Eudragit RSPO using a Hobart Mixer.-   2. Extrude the granulation using a Powder Feeder, Melt Extruder    (equipped with the 6×1 mm die head), Conveyor, Lasermike, and    Pelletizer.    -   Powder feed rate-40 g/min; vacuum-˜980 mBar    -   Conveyor-such that diameter of extrudate is 1 mm    -   Pelletizer-such that pellets are cut to 1 mm in length-   3. Screen pellets using #16 mesh and #20 mesh screens. Collect    material that passes through the #16 mesh screen and is retained on    the #20 mesh screen.-   4. Fill size #2 clear gelatin capsules with the pellets. Range: NLT    (not less than) 114 mg and NMT (not more than) 126 mg.

The sequestered naltrexone formulation of Example 9 can be incorporatedin a capsule with the hydrocodone pellets. Preferably, the sequesterednaltrexone pellets are indistinguishable from the hydrocodone pellets.

Releasable naltrexone can be a) overcoated onto the pellets by e.g.,including it in an Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an amount to have a desiredpharmacological effect as disclosed herein and can be immediate orsustained release.

One or more aversive agents as described herein can be incorporated intoa capsule with the hydrocodone pellets, into the hydrocodone pellets, oron the hydrocodone pellets by one skilled in the art. The one or moreaversive agents may be in releasable, non-releasable, or substantiallynon-releasable form or a combination thereof. Preferably, when pelletscomprising the aversive agent(s) are incorporated into the capsule theyare indistinguishable from the hydrocodone pellets.

Example 14 Oxycodone HCl Beads

A sustained release oxycodone HCl bead formulation was prepared havingthe formula in Table 14 below.

TABLE 14 Amt/unit* Ingredients (mg) Step 1. Drug layering Oxycodone HCl10.5 Non-pareil beads (30/35 mesh) 45.349 Opadry Clear 2.5 Step 2.Sustained release Eudragit RS30D (dry) 7.206 coat Eudragit RL30D (dry)0.379 Triethyl citrate 1.517 Cabosil 0.379 Step 3. Seal coat OpadryClear 1.899 (Hydroxypropylmethyl cellulose) Cabosil 0.271 Total 70.0

Process:

-   -   1. Dissolve oxycodone HCl and Opadry (HPMC) in water. Spray the        drug solution onto non-pareil beads in a fluid bed coater with        Wurster insert.    -   2. Disperse Eudragit RS, Eudragit RL, triethyl citrate, and        Cabosil in water. Spray the dispersion onto the beads in the        fluid bed coater.    -   3. Dissolve Opadry in water. Spray the solution onto the beads        in the fluid bed coater.    -   4. Cure the beads at 60° C. for 24 hours.

The sequestered naltrexone formulation of Example 8 can be incorporatedin a capsule with the oxycodone beads. Preferably, the sequesterednaltrexone beads are indistinguishable from the oxycodone beads.

Releasable naltrexone can be a) overcoated onto the pellets by e.g.,including it in an Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an amount to have a desiredpharmacological effect as disclosed herein and can be immediate orsustained release.

One or more aversive agents as described herein can be incorporated intoa capsule with the oxycodone beads, into the oxycodone beads, or on theoxycodone beads by one skilled in the art. The one or more aversiveagents may be in releasable, non-releasable, or substantiallynon-releasable form or a combination thereof. Preferably, when beadscomprising the aversive agent(s) are incorporated into the capsule theyare indistinguishable from the oxycodone beads.

Example 15 Controlled Release Hydromorphone

A sustained release hydromorphone HCl formulation was prepared havingthe formula in Table 15 below:

TABLE 15 Ingredients Amt/Unit (mg) Hydromorphone HCl 12.0 Eudragit RSPO76.5 Ethocel 4.5 Stearic acid 27.0 Total 120.0

Process:

-   -   1. Blend milled Stearic acid, ethocel, Hydrocodone Bitartrate,        and Eudragit RSPO using a V-blender.    -   2. Extrude the mixture using a Powder Feeder, Melt Extruder        (equipped with the 6×1 mm die head), Conveyor, Lasermike, and        Pelletizer.        -   Powder feed rate-4.2 kg/hr; vacuum-˜980 mBar        -   Conveyor-such that diameter of extrudate is 1 mm        -   Pelletizer-such that pellets are cut to 1 mm in length    -   3. Screen pellets using #16 mesh and #20 mesh screens. Collect        material that passes through the #16 mesh screen and is retained        on the #20 mesh screen.    -   4. Fill size #2 clear gelatin capsules with the pellets. Range:        NLT 114 mg and NMT 126 mg.

The sequestered naltrexone formulation of Example 15 can be incorporatedin a capsule with the hydromorphone pellets. Preferably, the sequesterednaltrexone pellets are indistinguishable from the hydrocodone pellets.

Releasable naltrexone can be a) overcoated onto the pellets by e.g.,including it in an Opadry solution, b) modifying the sequesteredcomponent to release the desired naltrexone, c) including the naltrexonewith the opioid agonist; or included in any other method known in theart. The amount of naltrexone should be in an amount to have a desiredpharmacological effect as disclosed herein and can be immediate orsustained release.

One or more aversive agents as described herein can be incorporated intoa capsule with the hydromorphone pellets, into the hydromorphonepellets, or on the hydromorphone pellets by one skilled in the art. Theone or more aversive agents may be in releasable, non-releasable, orsubstantially non-releasable form or a combination thereof. Preferably,when pellets comprising the aversive agent(s) are incorporated into thecapsule they are indistinguishable from the hydromorphone pellets.

Example 16 A 20 mg Oxycodone Dosage Form Containing Naloxone as theAntagonist and Multiple Deterring Agents is Prepared

Various deterring agents used in the previous examples are combined inone product to produce a tablet which could provide tampering resistanceto multiple types of abuse by the addicts. A small amount of naloxonehydrochloride, denatonium benzoate, and xanthan gum are added to anoxycodone formulation during the granulation process. The oxycodonegranulation formulation of Example 16 is listed in Table 16 below.

TABLE 16 Ingredients Amt/Unit (mg) Amount/Batch (gm) Oxycodone HCl 20.0209.6* Spray Dried Lactose 59.25 592.5 Povidone 5.0 50.0 Eudragit RS30D(solids) 10.0 100 Triacetin 2.0 20.0 Naloxone HCl 0.61 6.12** Denatoniumbenzoate 0.07 0.68 Xanthan gum 9.0 90.0 Stearyl Alcohol 25.0 250.0 Talc2.5 25.0 Magnesium Stearate 1.25 12.5 Opadry Pink Y-S-14518A 5.0 50.0*adjusted for 99.6% assay and 4.2% residual moisture. **adjusted for99.23% assay and 0.5% residual moisture.

Process

Dispersion: Dissolve naloxone HCl and denatonium benzoate in water andthe solution is added to the Eudragit/Tracetin dispersion.Granulation: Spray the Eudragit/Triacetin dispersion onto the OxycodoneHCl, Spray Dried Lactose, xanthan gum and Povidone using a fluid bedgranulator.Milling: Discharge the granulation and pass through a mill.Waxing: Melt the stearyl alcohol and add to the milled granulation usinga mixer. Allow to cool.Milling: Pass the cooled granulation through a mill.Lubrication: Lubricate the granulation with talc and magnesium stearateusing a mixer.Compression: Compress the granulation into tablets using a tablet press.

Example 17-20

Examples 4-7 can be repeated utilizing a sufficient amount of capsaicinin place of, or in addition to the aversive agents disclosed therein.

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that obvious modifications can be made herein withoutdeparting from the spirit and scope of the invention. Such variationsare contemplated to be within the scope of the appended claims.

1. An oral dosage form comprising: a therapeutically effective amount ofan opioid analgesic; an opioid antagonist; and an irritant in aneffective amount to impart a burning sensation to an abuser uponadministration of said dosage form after crushing, shearing, grinding,chewing, dissolution in a solvent, heating, or any combination thereof.2. The oral dosage form of claim 1, wherein the irritant is selectedfrom the group consisting of capsaicin, a capsaicin analog, and mixturesthereof.
 3. The oral dosage form of claim 1, wherein the irritant is acapsaicin analog selected from the group consisting of resiniferatoxin,tinyatoxin, heptanoylisobutylamide, heptanoyl guaiacylamide, otherisobutylamides or guaiacylamides, dihydrocapsaicin, homovanillyloctylester, nonanoyl vanillylamide, and mixtures thereof.
 4. The oraldosage form of claim 1, wherein the irritant is capsaicin.
 5. The oraldosage form of claim 1, wherein the irritant is vanillylamide.
 6. Theoral dosage form of claim 1, wherein the irritant is in a sequesteredform.
 7. The oral dosage form of claim 1, wherein the antagonist is in asequestered form.
 8. The oral dosage form of claim 1, wherein theantagonist and the irritant are both in sequestered forms.
 9. The oraldosage form of claim 1, wherein the irritant is in an amount of about0.00125% to about 50% by weight of the dosage form.
 10. The oral dosageform of claim 1, wherein the irritant is in an amount of about 1 toabout 7.5% by weight of the dosage form.
 11. The oral dosage form ofclaim 1, wherein the irritant is in an amount of about 1 to about 5% byweight of the dosage form.
 12. The oral dosage forms of claim 1, furthercomprising a pharmaceutically acceptable excipient.
 13. The oral dosagesform of claim 12, wherein said excipient is a sustained releaseexcipient.
 14. The oral dosage form of claim 12, said dosage formproviding an analgesic effect for at least about 12 hours after oraladministration to a human patient.
 15. The oral dosage form of claim 1,wherein said irritant is at least partially interdispersed with theopioid analgesic. 16-17. (canceled)
 18. The oral dosage form of claim 1wherein the antagonist is in an amount to attenuate a side effect ofsaid opioid agonist selected from the group consisting ofanti-analgesia, hyperalgesia, hyperexcitability, physical dependence,tolerance, and a combination of any of the foregoing. 19-24. (canceled)25. The oral dosage form of claim 1, wherein the opioid antagonist isnaloxone or a pharmaceutically acceptable salt thereof.
 26. The oraldosage form of claim 25, wherein the opioid analgesic is oxycodone or apharmaceutically acceptable salt thereof.
 27. The dosage form of claim26, wherein the dosage form is a controlled release oral dosage form.28. The dosage form of claim 27, wherein the dosage form provideseffective pain relief for about 12 hours.